N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors

ABSTRACT

Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. TNF-α converting enzyme (TACE), a pro-inflmatory cytokine, catalyzes the formation of TNF-α from membrane bound TNF-α precursor protein. It is expected that small molecule inhibitors of MMPs and TACE therefore have the potential for treating a variety of disease states. The present invention provides low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-α converting enzyme (TACE) for the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection having the formula                    
     wherein R 2  and R 3  form a heterocyclic ring and A is S, S(O), or S(O) 2 , and R 1  and R 4  are defined herein.

This is a divisional of copending application(s) Ser. No. 09/587560filed on Jun. 5, 2000 (now Pat. No. 6,331,563), which is a divisional ofSer. No. 09/140,504 filed Aug. 26, 1998 (now U.S. Pat. No. 6,197,791),which is a continuation-in-part of U.S. Ser. No. 09/026,372 filed Feb.19, 1998, which claims the benefit of U.S. Ser. No. 60/038,899 filedFeb. 27, 1997; the entire disclosure of each prior application is herebyincorporated by reference.

BACKGROUND OF THE INVENTION

Matrix metalloproteinases (MMPs) are a group of enzymes that have beenimplicated in the pathological destruction of connective tissue andbasement membranes. These zinc containing endopeptidases consist ofseveral subsets of enzymes including collagenases, stromelysins andgelatinases. Of these classes, the gelatinases have been shown to be theMMPs most intimately involved with the growth and spread of tumors. Itis known that the level of expression of gelatinase is elevated inmalignancies, and that gelatinase can degrade the basement membranewhich leads to tumor metastasis. Angiogenesis, required for the growthof solid tumors, has also recently been shown to have a gelatinasecomponent to its pathology. Furthermore, there is evidence to suggestthat gelatinase is involved in plaque rupture associated withatherosclerosis. Other conditions mediated by MMPs are restenosis,MMP-mediated osteopenias, inflammatory diseases of the central nervoussystem, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis,septic arthritis, corneal ulceration, abnormal wound healing, bonedisease, proteinuria, aneurysmal aortic disease, degenerative cartilageloss following traumatic joint injury, demyelinating diseases of thenervous system, cirrhosis of the liver, glomerular disease of thekidney, premature rupture of fetal membranes, inflammatory boweldisease, periodontal disease, age related macular degeneration, diabeticretinopathy, proliferative vitreoretinopathy, retinopathy ofprematurity, ocular inflammation, keratoconus, Sjogren's syndrome,myopia, ocular tumors, ocular angiogenesis/neo-vascularization andcorneal graft rejection. For recent reviews, see: (1) Recent Advances inMatrix Metalloproteinase Inhibitor Research, R. P. Beckett, A. H.Davidson, A. H. Drummond, P. Huxley and M. Whittaker, Research Focus,Vol. 1, 16-26, (1996), (2) Curr. Opin. Ther. Patents (1994) 4(1): 7-16,(3) Curr. Medicinal Chem. (1995) 2: 743-762, (4) Exp. Opin. Ther.Patents (1995) 5(2): 1087-110, (5) Exp. Opin. Ther. Patents (1995)5(12): 1287-1196.

TNF-α converting enzyme (TACE) catalyzes the formation of TNF-α frommembrane bound TNF-α precursor protein. TNF-α is a pro-inflammatorycytokine that is now thought to have a role in rheumatoid arthritis,septic shock, graft rejection, cachexia, anorexia, inflammation,congestive heart failure, inflammatory disease of the central nervoussystem, inflammatory bowel disease, insulin resistance and HIV infectionin addition to its well. documented antitumor properties. For example,research with anti- TNF-α antibodies and transgenic animals hasdemonstrated that blocking the formation of TNF-α inhibits theprogression of arthritis. This observation has recently been extended tohumans as well.

It is expected that small molecule inhibitors of MMPs and TACE thereforehave the potential for treating a variety of disease states. While avariety of MMP and TACE inhibitors have been identified and disclosed inthe literature, the vast majority of these molecules are peptidic andpeptide-like compounds that one would expect to have bioavailability andpharmacokinetic problems common to such compounds that would limit theirclinical effectiveness. Low molecular weight, potent, long acting,orally bioavailable inhibitors of MMPs and/or TACE are therefore highlydesirable for the potential chronic treatment of the above mentioneddisease states.

Recently, two references have appeared (U.S. Pat. No. 5,455,258 andEuropean Patent Appl. 606,046) that disclose arylsulfonamido-substitutedhydroxyamic acids. These documents cover compounds exemplified by CGS27023A. These are the only non-peptide matrix metalloproteinaseinhibitors disclosed to date.

Salah et al., Liebigs Ann. Chem. 195, (1973) discloses some arylsubstituted thio and aryl substituted sulfonyl acetohydroxamic acidderivatives of general formula 1. These compounds were prepared to studythe Mannich reaction. Subsequently, they were tested for theirfungicidal activity.

Some sulfone carboxylic acids are disclosed in U.S. Pat. No. 4,933,367.Those compounds were shown to exhibit hypoglycemic activity.

SUMMARY OF THE INVENTION

The present invention relates to novel, low molecular weight,non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-αconverting enzyme (TACE) for the treatment of arthritis, tumormetastasis, tissue ulceration, abnormal wound healing, periodontaldisease, bone disease, diabetes (insulin resistance) and HTV infection.

In accordance with this invention there is provided a group of compoundsof general formula I

wherein:

R¹ is alkyl of I to 18 carbon atoms, optionally substituted with one ortwo groups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;

aryl of 6 to 10 carbon atoms, optionally substituted with one or twogroups selected independently from R⁵;

cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one ortwo groups selected independently from R⁵;

saturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷, optionallysubstituted with one or two groups selected independently from R⁵;

or heteroaryl-(CH₂)₀₋₆— wherein the heitroayl group is 5 to 6 memberedwith one or two heteroatoms selected independently from O, S, and N andmay be optionally substituted with one or two groups selectedindependently from R⁵;

A is —S—, —SO— or SO₂—;

R² and R³, taken with the carbon atom to which they are attached, form a5 to 7 membered heterocyclic ring contaning O, S or N—R⁷ optionallyhaving one or two double bonds;

R⁴ is hydrogen,

alkyl of 1 to 6 carbon atoms, optionally substituted with one or twogroups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;

phenyl or naphthyl optionally substituted with one or two groupsselected independently from R⁵;

C₃ to C₈ cycloalkyl or bicycloalkyl optionally substituted with one ortwo groups selected independently from R⁵;

saturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷, optionallysubstituted with one or two groups selected independently from R⁵;

R⁵ is H, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alkyl, C₂ to C₁₂alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy, aryloxy,heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ allyloxy, C₁-C₆ alkoxyaryl, C₁-C₆alkoxyheteroaryl, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂ alkylene dioxy,aryloxy-C₁-C₆ alkyl amine, C₁-C₁₂ perfluoro alkyl, S(O)_(n)—C₁-C₆ alkyl,S(O)_(n)-aryl where n is 0, 1 or 2; OCOO C₁-C₆ ayl, OCOOaryl, OCONR⁶,COOH, COO C₁-C₆ alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶,NR⁶SO₂aryl, —NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl,SO₂NHCOaryl,CONHSO₂-C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂-C₁-C₆ alkyl,CONHSO₂aryl, NH₂, OH, aryl, heteroaryl, C₃ to C₈ cycloalkyl; orsaturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR^(7,) wherein C₁-C₆

alkyl is straight or branched, heteroaryl is a 5-10 membered mono orbicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or NR⁷ and aryl is phenyl or naphthyl,optionally substituted by 1 or 2 groups selected from halogen, cyano,amino, nitro, C₁-C₆ alyl, C₁-C₆ alkoxy, or hydroxy;

R⁶ is H, C₁ to C₈ alkyl optionally substituted with OH; C₃ to C₆alkenyl, C₃ to C₆ alkyl, C₁ to C₆ perfluoro alkyl, S(O)_(n)-C₁-C₆ alkylS(O)_(n) aryl where n is 0, 1 or 2;, or COheteroaryl, wherein heteroarylis a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3heteroatoms selected independently from O, S or NR⁷ and aryl is phenylor naphthyl, optionally substituted by 1 or 2 groups selected fromhalogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy;

and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl,S(O)_(n)—C₁-C₆-alkyl, S(O)_(n)-aryl where n is 0, 1 or 2;COO-C₁-C₆-alkyl, COOaryl, CONR6, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF₃,SO₂NHheteroaryl, SO₂NHCOaryl, CONHSO-C₁-C₆-alkyl, CONHSO₂aryl, aryl, orheteroaryl, where aryl is phenyl or naphthyl, optionally substituted by1 or 2 groups selected independently from halogen, cyano, amino, nitro,C₁-C₆ alkyI, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 memberedmono or bicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or N—C₁-C₆ alkyl;

alkyl of 1 to 18 carbon atoms, optionally substituted with one or twogroups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds,optionally substituted with one or two groups selected independentlyfrom R⁵;

alkynyl 3 to 8 carbon atoms having from 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;

arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;

heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroarylcontains 1 or 2 heteroatoms selected from O, S or N and is optionallysubstituted with one or two groups selected independently from R⁵;

biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionallysubstituted with one or two groups selected independently from R⁵;

arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;

cycloalkylalyl or bicycloalylakyl of 4 to 12 carbon atoms, wherein thecycloalkyI or bicycloalkyl group is optionally substituted with one ortwo groups selected independently from R⁵;

saturated or unsaturated mono or bicyclic heterocycle containilg oneheteroatom selected from O, S or N—C₁-C₆ alky, optionally substitutedwith one or two groups selected independently from R⁵; or

R⁸R⁹N-C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ and R⁹ are independentlyselected from C₁-C₆ alkl or R⁸ and R⁹ together with the interposednitrogen forms a 5-7 membered saturated heterocyclic ring optionallycontaining an oxygen atom, wherein the aryl group is phenyl or naphthyl;

and the pharmaceutically acceptable salts thereof.

A more preferred aspect of the present invention is the group ofcompounds of general formula (Ia):

wherein:

R¹ is alkl of 1 to 18 carbon atoms, optionally substituted with one ortwo groups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;

aryl of 6 to 10 carbon atoms, optionally substituted with one to twogroups selected independently from R⁵;

cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one totwo groups selected independently from R⁵;

saturated or unsaturated mono or bicyclic heterocycle of from 5 to 10members containing one heteroatom selected from O, S or NR⁷, optionallysubstituted with one to two groups selected independently from R⁵;

or heteroaryl-(CH₂)₀₋₆- wherein the heteroaryl group is 5 to 6 memberedwith one or two heteroatoms selected independently from O, S, and N andmay be optionally substituted with one or two groups selectedindependently from R⁵;

A is —S—, —SO— or SO₂—;

R² and R³, taken with the carbon atom to which they are attached, form a5 to 7 membered heterocyclic ring containing O, S or N—R⁷ optionallyhaving one or two double bonds;

R⁴ is hydrogen,

alkyl of 1 to 6 carbon atoms, optionally substituted with one or twogroups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently fronm R⁵;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;

phenyl or naphthyl optionally substituted with one or two groupsselected independently from R⁵;

C₃ to C₈ cycloalkyl or bicycloalkyl optionally substituted with one ortwo groups selected independently from R⁵;

R⁵ is H, F, Cl, Br, I, CN, CHO, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂alkyl, C₂ to C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₆ alkoxy, aryloxy,heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alknyloxy, C₁-C₆ alkoxyaryl,C₁-C₆ alkoxyheteroaryl, C₁-C₆-alkylamino-C₁-C₆ alkoxy, C₁-C₂-alkylenedioxy, aryloxy-C₁-C₆ alkyl amine, C₁-C₁₂perfluoro alkyl, S(O)_(n)-C₁-C₆alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; OCOO-C₁-C₆ alkyl, OCOaryl,OCONR⁶, COOH, COO-C₁-C₆ alyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶,NR⁶SO₂aryl, NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl, SO₂NHCOaryl,CONHSO₂-C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂-C₁-C₆ alkyl,CONHSO₂aryl, NH₂, OH, aryl, heteroaryl, C₃ to C₈ cycloalkyl; orsaturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷;

wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl grouphaving 1 to 3 heteroatoms selected independently from O, S or NR⁷ andaryl is phenyl or naphthyl, optionally substituted by 1 or 2 groupsselected independently from halogen, cyano, amino, nitro, C₁-C₆ alkyl,C₁-C₆ alkoxy, or hydroxy;

R⁶ is H, C₁ to C₁₈ alkyl optionally substituted with OH; C₃ to C₆alkenyl, C₃ to C₆ alkynyl, C₁ to C₆ perfluoro alkyl, S(O)_(n) alkyl oraryl where n is 0, 1, or 2; or COheteroaryl;

wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl grouphaving 1 to 3 heteroatoms selected independently from 0, S or NR⁷ andaryl is phenyl or naphthyl, optionally substituted by 1 or 2 groupsselected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy,or hydroxy;

and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl,S(O)_(n)-alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; COalkyl, COOaryl,CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶,SO₂CF₃, SO₂NHheteroaryl, SO₂NHCOaryl,CONHSO₂alkyl, CONHSO₂aryl, aryl, heteroaryl; wherein C₁-C₆ alkyl isstraight or branched, heteroaryl is a 5-10 membered mono or bicyclicheteroaryl group having 1 to 3 heteroatoms selected independently fromO, S or NR⁷ and aryl is phenyl or naphthyl, optionally substituted by 1or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl,C₁-C₆ alkoxy, or hydroxy;

alkyl of 1 to 18 carbon atoms, optionally substituted with one or twogroups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds,optionally substituted with one or two groups selected independentlyfrom R⁵;

alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds,optionally substituted with one or two groups selected independentlyfrom R⁵;

arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;

heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroarylcontains 1 or 2 heteroatoms selected from O, S or N and is optionallysubstituted with one or two groups selected independently from R⁵;

biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionallysubstituted with one or two groups selected independently from R⁵;

arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;

cycloalkylalkyl or bicycloalrlalkyl of 4 to 12 carbon atoms, whereincycloalkyl or bicycloalkyl is optionally substituted with one or twogroups selected independently from R⁵;

saturated or unsaturated mono or bicyclic heterocycle containing oneheteroatom selected from O, S or N-C₁-C₆ alkyl, optionally substitutedwith one or two groups selected independently from R⁵;

R⁸R⁹N-C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ and R⁹ are independentlyselected from C₁-C₆ alkyl or R⁸ and R⁹ together with the interposednitrogen forms a 5-7 membered saturated heterocyclic ring optionallycontaining an oxygen atom, wherein the aryl group is phenyl or naphthyl;

and the pharmaceutically acceptable salts thereof.

The most preferred group of compounds are those of the following formula(Ib):

in which

R¹ is phenyl, naphthyl, alkyl of 1-18 carbon atoms or heteroaryl such aspyridyl, dienyl, imidazolyl or furanyl, optionally substituted withC₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ aryloxy, heteroaryloxy, C₃-C₆alkenyloxy, C₃-C₆ alkyloxy, halogen; or S(O)_(n)-C₁-C₆alkyl C₁-C₆alkoxyaryl or C₁-C₆ alkoxyheteroaryl;

A is —S—, —SO or —SO₂—;

R² and R³, taken with the carbon atom to which they are attached, form a5 to 7 membered heterocyclic ring containing O, S or N—R⁷ optionallyhaving one or two double bonds;

R⁴ is hydrogen,

alkyl of 1 to 6 carbon atoms, optionally substituted with one or twogroups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;

phenyl or naphthyl optionally substituted with one or two groupsselected independently from R⁵;

C₃ to C₈ cycloalkyl or bicycloallyl optionally substituted with one ortwo groups selected independently from R⁵;

R⁵ is H, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alkyl, C₂ to C₁₂alkenyl, C₂-C₁₂ allynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy, aryloxy,heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆alkylamino-C₁-C₆ alkoxy, C₁-C₂ alkylene dioxy, aryloxy-C₁-C₆ alkylamine, C₁-C₁₂ perfluoro alkyl, S(O)_(n)-C₁-C₆ alkyI, S(O)_(n)-aryl wheren is 0, 1 or 2; OCOO C₁-C₆ aLkyl, OCOOayl, OCONR⁶, COOH, COO C₁-C₆alkyl, COaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂N ⁶R⁶, NR⁶SO₂aryl —NR⁶CONR⁶R⁶,NHSO₂CF₃, SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂-C₁-C₆ alkyl, CONHSO₂aryl,SO₂NHCOaryl, CONHSO₂-C₁-C₆ alkyI, CONHSO₂aryl, NH₂, OH, aryl,heteroaryl, C₃ to C₈ cycloalkyl; saturated or unsaturated 5 to 10membered mono or bicyclic heterocycle containing one heteroatom selectedfrom O, S or NR⁷, wherein C₁-C₆ aLkyl is straight or branched,heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy;

R⁶ is H, C₁ to C₁₈ alkyl optionally substituted with OH; C₃ to C₆alkenyl, C₃ to C₆ alkynyl, C₁ to C₆ perfluoro alkyl, S(O)_(n) alkyl oraryl where n is 0, 1 or 2; or COheteroaryl; wherein heteroaryl is a 5-10membered mono or bicyclic heteroaryl group having 1 to 3 heteroatomsselected independently from O, S or NR⁷ and aryl is phenyl or naphthyl,optionally substituted by 1 or 2 groups selected from halogen, cyano,amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy;

and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl,S(O)_(n)-alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; COOalkl, COOarylCONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶,SO₂CF₃, SO₂NHheteroaryl, SO₂NHCOaryl,CONHSO₂alkyI, CONHSO₂aryl aryl, or heteroaryl; where aryl is phenyl ornaphthyl, optionally substituted by 1 or 2 groups selected independentlyfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroarylgroup having 1 to 3 heteroatoms selected independently from O, S orN—C₁-C₆ alkyl;

alkyl of 1 to 18 carbon atoms, optionally substituted with one or twogroups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds,optionally substituted with one or two groups selected independentlyfrom R⁵;

alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds,optionally substituted with one or two groups selected independentlyfrom R⁵;

arylalkyl of 7 to 16 carbon atoms, optionally substituted with one ortwo groups selected independently from R⁵;

heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroarylcontains 1 or 2 heteroatoms selected from O, S or N and is optionallysubstituted with one or two groups selected independently from R⁵;

biphenylalkyl of 13 to 18 carbon atoms, optionally substituted with oneor two groups selected independently from R⁵;

arylalkenyl of 8 to 16 carbon atoms, optionally substituted with one ortwo groups selected independently from R⁵;

cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;

saturated or unsaturated mono or bicyclic heterocycle containing oneheteroatom selected from O, S or NR-C₁-C₆ alkyl, optionally substitutedwith one or two groups selected independently from R⁵;

R⁸R⁹N-C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ and R⁹ are independentlyselected from C₁-C₆ alkyl or R⁸ and R⁹ together with the interposednitrogen forms a 5-7 membered saturated heterocyclic ring optionallycontaining an oxygen atom, wherein the aryl group is phenyl or naphthyl;

and the pharmaceutically acceptable salts thereof.

The most preferred matrix metalloproteinase and TACE inhibitingcompounds of this invention are:

1-benzyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxyamide,

1-(3,4-dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxamide,

4-(4methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide,

4-(4-methoxy-benzene-sulfonyl)-1-napthalene-2-yl-methylpiperidine-4-carboxylicacid hydroxamide,

1-biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylicacid hydroxamnide,

4-(4-methoxy-benzene-sulfonyl)-1-(3-methyl-but-2-enyl)piperidine-4-carboxylicacid hydroxamide,

1-(4-bromo-benzyl)4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylicacid hydroxyamide,

1-tert-butyl-4-(4methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-cyclooctyl-4-(4methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-ethyl-4-(4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyarnide,

1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine4-carboxylic acidhydroxyamide,

1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide,

1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)ethyl]-piperidine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-n-butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-n-butoxy-benzenesulfonyl)-1-(2phenoxyethyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid hydroxyamide,

1-Benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid hydroxyamide,

4-(4-Butoxy-benzenesulfonyl)-1-[3-(2-morpholinyl-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid hydroxyamide,

1-Methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

4-[4-(4-chloro-phenoxy)-benzenesulfonyl]1-methyl-piperidine-4-carboxylicacid hydroxyamide,

4-[4-(4-chlorophenoxy)-benzenesulfonyl]1-ethyl-piperidine-4-carboxylicacid hydroxyamide,

1-Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide,

1-Benzyl-4-[4-(4-chorophenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide,

1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide,

1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide,

1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide,

4-(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-Methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperdine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylicacid hydroxyamide,

1-(3,4-Dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide,

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylicacid hydroxamide,

4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylicacid hydroxamide,

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide,

4-(4-Butoxy-benzenesulfonyl)-1-(4methylbenzyl)-piperidine-4-carboxylicacid hydroxamide,

4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylicacid hydroxamide, and

4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylicacid hydroxamide, and pharmaceutical salts thereof.

It is understood that the definition of the compounds of formulas I, Iaand lb, when R¹, R², R³ and R⁴ contains asymmetric carbons, encompassall possible stereoisomers and mixtures thereof which posses theactivity discussed below. In particular, it encompasses racemicmodifications and any optical isomers which possesses the indicatedactivity. Optical isomers may be obtained in pure form by standardseparation techniques. Where not stated otherwise, the term “alkyl”refers to a straight or branched C₁-C₆ alkyl group and aryl is phenyl ornaphthyl. The ph&mceutically acceptable salts are those derived frompharmaceutically acceptable organic and inorganic acids such as lactic,citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric,hydrobromic, phosphoric, nitric, sulfiric, methanesulfonic, andsimilarly known acceptable acids.

The present invention accordingly provides a pharmaceutical compositionwhich comprises a compound of this invention in combination orassociation with a pharmaceutically acceptable carrier. In particular,the present invention provides a pharmaceutical composition whichcomprises an effective amount of compound of this invention and apharmaceutically acceptable carrier.

The compositions are preferably adapted for oral administration.However, they may be adapted for other modes of administration, forexample, parenteral administration for patients.

In order to obtain consistency of administration, it is preferred that acomposition of the invention is in the form of a unit dose. Suitableunit dose forms include tablets, capsules, and powders in sachets orvials. Such unit dose forms may contain from 0.1 to 100 mg of a compoundof the invention. The compounds of the present invention can beadministered orally at a dose range of about 0.01 to 100 mg per kg. Suchcomposition may be administered from 1 to 6 times a day, more usuallyfrom 1 to 4 times a day.

The compositions of the invention may be formulated with conventionalexcipients, such as fillers, a disintegrating agent, a binder, alubricant, a flavoring agent, and the like. They are formulated inconventional manner.

Also according to the present invention, there are provided processesfor producing the compounds of the present invention.

PROCESS OF THE INVENTION

The compounds of the present invention may be prepared according to oneof the general processes out lined below.

The appropriately substituted mercaptan derivative was allated usingeither substituted (Scheme I) or unsubstituted ( Scheme 2) α-bromoacetic acid ester derivative in refluxin acetone using K₂CO₃ as base.The sulphide derivative thus obtained was oxidized usingm-chloroperbenzoic acid in CH₂Cl₂ or by using Oxone in methanol/water.The sulfone obtained from the above mentioned process can be eitherfilrter alkylated using variety of alkyl halides to obtain thedisubstituted derivative or it can be hydrolyzed using NaOH/MeOH at roomtemp. However instead of using the ethyl ester, if the tertiary butylester is present, the hydrolysis can be carried out with TFA/CH₂Cl₂ atroom temperature. Subsiquently, the carboxylic acid obtained wasconverted to the hydroxamic acid derivative by reaction with oxalylchloride/DMX (catalytic) and hydroxyl amine/triethyl amine.

As outlined in Scheme 3, the sulfide derivative can be flirter allylatedusing lithium bis(trimethyl silyl)amide in THF at 0° C. The alkylated ormono substituted compound was hydrolyzed and converted to the hydroxamicacid derivative. The sulfinyl derivatives were prepared by oxidizing thesulfide hydroxamic acid derivatives with H₂O₂ in MeOH solution.

The corresponding1-substituted-4-(4methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamides were prepared startng from diethanolamine andappropriately substituted alkyl or aryl halides (Scheme 4). TheN-substituted diethanol amine derivatives were converted to the dichiorocompounds using thionyl chloride. The corresponding dichlorides werereacted with substituted sulfonyl acetic acid ethyl ester derivatives inthe presence of K₂CO₃/18-Crown-6 in boiling acetone.1-substituted-4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl esters thus obtained were converted to the hydroxy amide asoutlined in Scheme 4. Alternatively these classes of compounds and otherhetrocycles can be prepared as indicated in Scheme 5 and 6.

Alternatively, Schemes 7 to 11 show methods for the preparation ofhydroxamic acid compounds using a solid phase support (P).

Reagents and Conditions: a) 2-Halo acid (3.0 eq.);1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.);1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25° C.; 2-16 hours. b)Thiol (5.0 eq.); sodium iodide (5.0 eq.);1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0 eq.); THF; 25° C.; 12-16hours. c) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid(2.0 eq.); DCM; 25° C.; 12-24 hours. d) mCPBA (5.0 eq.); DCM; 25° C.;12-24 hours. e) TFA: DCM (1:1); 25° C.; 1 hour.

The4-O-methylhydroxylamine-phenoxymethylopoly(styrene-1%-divinylbenzene)-resin(hydroxylamine resin) may be coupled with a 2-halo acid to give thehydroxamate ester resin. The coupling reaction may be carried out in thepresence of carbodiimide, such as DIC, in an inert solvent such as DMFat room temperature. The halogen group may be displaced with a thiol inthe presence of a base, such as DBU, in an inert solvent such as THF atroom temperature. The sulfide may be oxidized to the sulfoxide byreaction with an oxifig agent such as tert-butylhydroperoxide in thepresence of an acid catalyst such as benzenesulfonic acid, in an inertsolvent such as DCM at room temperature. Alternatively, the sulfide maybe oxidized to the sulfone by reaction with an oxidizing agent such asmeta-chloroperoxybenzoic acid, in an inert solvent such as DCM at roomtemperature. The sulfide, sulfoxide, or sulfone may be treated with andacid, such as trifluoroacetic acid, in and inert solvent such as DCM tohlberate the fee hydroxamic acid.

Scheme 8 shows a method of preparing hydroxamic acids having alkoxygroups attached to the aromatic ring.

Reagents and Conditions: a) 2-Halo acid (3.0 eq.);1-hydroxybenzotriazole hydrate (HOBt, 6,0 eq.)1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25° C.; 2-16 hours. b)4-Fluorobenzenethiol (5.0 eq.;) sodium iodide (5.0 eq.);1,8-diazabicycle[5.4.0]undec-7-ene (DBU, 3.0 eq.); THF; 25° C.; 12-16hours. c) Alcohol (15.0 eq.); sodium hydride (15.0 eq.); DMF; 80° C.; 15hours. d) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid(2.0 eq.); DCM; 25° C.; 12-24 hours. e) mCPBA (5.0 eq.); DCM; 25° C.;12-24 hours. f) TFA: DCM (1:1); 25° C.; 1 hour.

The hydroxylainie resin may be coupled with the 2-halo acid and the halogroup may be displaced by fluorobenzenethiol as previously described.The fluoro group may then be displaced with an alcohol in the presenceof a base such as sodium hydride, in an inert solvent such as DMF atabout 80° C. The alkoxybenzenesulfanyl hydroxamate ester may then beoxidized either to the corresponding sulfinyl or sulfonyl hydroxamateester as previously described. The free hydroxamic acids may beliberated as previously descnied

Scheme 9 shows a method of preparing 2-bisarylsulfanyl-, sulfinyl-, andsulfonylhydroxamic acids.

Reagents and conditions: a) 2-Halo acid (3.0 eq.);1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.);1,3-diisopropylcarbodiiliimde (DIC, 4.0 eq.); DMF, 25° C.; 2-16 hours.b) 4-Bromobenzenethiol (5.0 eq.); sodium iodide (5.0 eq.);1,8diazabicyclo[5.4.0]undec-7ene (DBU, 3.0 eq.); THF; 25° C.; 12-16hours. c) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid(2.0 eq.); DCM; 25° C.; 12-24 hours. d) mCPBA (5.0 eq.); DCM; 25° C.;12-24 hours. e) Arylboronic acid (2.0 eq.);tetrakis(triphenylphospliine) palladium(0) (0.1 eq.); 10% aqueous sodiumcarbonate (10.0 eq.); DME; 80° C.; 8 hours. f) TFA: DCM (1:1); 25° C.; 1hour.

The hydroxylamine resin may be coupled with the 2-halo acid and the halogroup may be displaced by bromobenzenethiol as previously described. Thebromobenzenesulfanyl hydroxamate ester may then be oxidized either tothe corresponding sulfinyl or sulfonyl hydroxamate ester as previouslydescribed. The bromo group may then be replaced with an aryl group byreaction with the arylboronic acid in the presence of a catalyst such astetrakis(triphenylphosphine) palladium(0), and a base such as sodiumcarbonate, in anl inert solvent such as DME at about 80° C. The freehydroxamic acids may be liberated as previously described.

Scheme 10 shows a method of preparing hydroxamic acids having aminegroups attached to the aromatic ring.

Reagents and Conditions: a) 2-Halo acid (3.0 eq.);1-hydroxybenzotiiazole hydrate (HOBt, 6.0 eq.);1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25° C.; 2-16 hours. b)4-Bromobenzenethiol (5.0 eq.); sodium iodide (5.0 eq.);1,8-diazabicyclo[5.4.0]undec-7ene (DBU, 3.0 eq.); TBF; 25° C.; 12-16hours. c) Amine (20.0 eq.); tris(dibenzylideneacetone)-dipalladium(0)(0.2 eq.); (S)-(−)-2,2′-bis(diphenylphosphimo)-1,1′-binaphthyl((S)-BINAP, 0.8 eq.); sodium tert-butoxide (18.0 eq.); dioxane; 80° C.,8 hours; d) TFA: DCM (1:1); 25° C.; 1 hour.

The hydroxylamine resin may be coupled with the 2-halo acid and the halogroup may be displaced by bromobenzenethiol as previously described. Thebromo group may then be displaced with an amine in the presence of acatalyst such as tds(dibenzylideneacetone)-dipalladium(0) and a ligandsuch as (S)-BINAP and a base such as sodium tert-butoxide, in an inertsolvent such as dioxane at about 80° C. The free hydroxarnic acids maybe hberated as previously described.

Scheme 11 shows a method of preparing hydroxamic acids having sulfonategroups attached to the aromatic ring.

Reagents and Conditions: a) 2-Halo acid (3.0 eq.);1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.);1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25° C.; 2-16 hours. b)4-Hydroxybenzenethiol (5.0 eq.); sodium iodide (5.0 eq.);1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0 eq.); THF; 25° C.; 12-16hours. c) Sulfonyl chloride (5.0 eq.); triethylamine (2.0 eq.); DCM; 25°C.; 8 hours. d) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonicacid (2.0 eq.); DCM; 25° C.; 12-24 hours. e) mCPBA (5.0 eq.); DCM; 25°C.; 12-24 hours. f) TFA: DCM (1:1); 25° C.; 1 hour.

The hydroxylanmine resin may be coupled with the 2-halo acid and thehalo group may be displaced by hydroxybenzenethiol as previouslydescribed. The hydroxybenzenesulfanyl hydroxamate ester may then beoxidized either to the corresponding sulfinyl or sulfonyl hydroxamateester as previously described. The hydroxy group may then besulfonylated by reaction with a sulfonyl chloride in the presence of abase such as triethylamine, in an inert solvent such as DCM at aboutroom temperature. The free hydroxamic acids may be liberated aspreviously described.

The following examples are presented to illustrate rather than limit thescope of the invention. HPLC purity of compounds prepared bycombinatorial procedures is presented as area percentage at a prescribedwavelength (% @ nm).

EXAMPLE 1

N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamnide

To stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mmol) andanhydrous K₂CO₃ (10 gm, excess) in dry acetone (100 ml), ethyl2-bromo-propionate (3.6 gm, 20 mmol) was added in a round bottom flaskand the reaction mixture was heated at reflux for 8 hours with goodstirring. At the end, reaction was allowed to cool and the potassiumsalts were filtered off and the reaction mixture was concentrated Theresidue was extracted with chloroform and washed with H₂O and 0.5 N NaOHsolution. The organic layer was further washed well with water, driedover MgSO₄, filtered and concentrated to afford2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester as a lightyellow oil. Yield 4.5gms (94%); MS; 241 (M+H)⁺.

To a stirred solution of 2-(4-methoxy-phenylsulfanyl)-propionic acidethyl ester (2.44 g, 10 mmol), in THF (100 ml) at −4° C., lithiumbis(trimethylsilyl)amide (1 M solution, −15 ml, 15 mmol) was addedslowly. The orange colored reaction mixture was stirred at roomtemperature for 15 minutes and then it was cooled to 0° C. at which timeit was stirred for an additional hour.

The temperature of the mixture was again brought to −40° C. andbenzylbromide (1.72 gm, 10 mmol) was added dropwise in THF. The reactionwas warmed to room temperature and stirred overnight before it wasquenched with ice water, extracted with chloroform and washed withwater. The organic layer was dried over MgSO₄, filtered and concentratedand chromatographed on a silica-gel column with 10% ethyl acetate:hexaneto afford 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acidethyl ester as a colorless oil. Yield: 860 mg, (26%); MS: 331 (M+H)⁺.

2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid ethylester (4.12 g, 12 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20ml) was added. The reaction was allowed to stir overnight at roomtemperature. The reaction mixture was concentrated, diluted with 1:1hexane:diethyl ether and extracted with H₂O. The water layer was cooledwith ice and acidified to pH 3. The acid was then extracted withchloroform and the organic layer was dried over MgSO₄, filtered andconcentrated to afford of2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid as a lowmelting solid. Yield 580 mg, 16%; MS: 303.2 (M+H)⁺.

To a stirred solution of2-(4methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid (0.5 g,1.65 mmol) and DEF (2 drops) in CH₂Cl₂ (100 ml) at 0° C., oxalylchloride (1.0 gm, 8 mmol) was added in a drop-wise manner. After theaddition, the reaction mixture was stirred at room temperature for 1hour. Simultaneously, in a separate flask a mixture of hydroxylaminehydrochloride (2.0 gm, 29 mmol) and triethylamine (5 ml, excess) wasstirred in THF:water (5:1, 30 ml) at 0° C. for 1 hour. At the end of 1hour, the oxalyl chloride reaction mixture was concentrated and the paleyellow residue was dissolved in 10 ml of CH₂Cl₂ and added slowly to thehydroxylamine at 0° C. The reaction mixture was stirred at roomtemperature for 24 hours and concentrated. The residue obtained wasextracted with chloroform and washed well with water. The productobtained was purified by silica gel column chromatography and elutedwith ethyl acetate. TheN-hydroxy-2-(4-methoxyphenylsulfanyl)-2-methyl-3-phenyl-propionamide wasisolated as a colorless solid. mp 88° C.; Yield, 300 mg, 57%; MS: 318(M+H)⁺; 1H NMR (300 MHz, CDCl₃): δ 1.32 (s, 3H), 3.07 (d, J =11 Hz, 1H),3.23 (d, J=11 Hz, 1H), 3.79 (s, 3H), 6.83-7.36 (m, 9H).

EXAMPLE 2

N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide

2-(4-Methoxyphenylsulfanyl)-phenylacetic acid ethyl ester was preparedaccording to the general method as outlined in Example 1. Staring fromethyl a-bromophenyl acetate (7.18 g, 31.4 mmol) and 4-methoxythiophenol(4.4 g, 31.4 mmol), 8.5 g of the product was isolated as a light yellowoil. Yield 90%; MS: 303.1 (M+H)⁺.

2-(4-Methoxy-phenylsulfanyl)-2-phenyl acetic acid was prepared startingfrom 2-(4-methoxy-phenylsulfanyl)-phenyl-acetic acid ethyl ester (3.0 g,10 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20 ml). Theresulting reaction mixture was worked up as in Example 1. Yield 1.9 g,70%. Low melting solid. MS: 273 (M+H)⁺.

Starting from 2-(4-methoxy-phenylsulfanyl)-phenyl acetic acid (1.05 g,3.83 mmol) and following the procedure as outlined in Example 1, 154 mgof N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetnmide wasisolated as a colorless solid. mp 155° C.; Yield 14%; MS: 290 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆): δ 3.72 (s, 3H), 4.68 (s, 1H), 6.86-7.44 (m, 9H).

EXAMPLE 3

2-(4-Methoxy-phenylsulfanyl)-2,5 -dimethyl-hex-4-enoic acid hydroxyamide

2-(4-Methoxy-phenylsulfanyl)-2,5-dimethyl-hexenoic acid ethyl ester wasprepared following the procedure of Example 1, second paragraph.Starting from (4-methoxy-phenylsulfanyl)-propionic acid ethyl ester (3.5g, 14.3 mmol), and isoprenyl bromide (2.25 g, 15 mmol), 2.2 g of theproduct was isolated as an oil. Yield 50%; MS: 310 (M+H)⁺.

2-(4-Methoxy-phenylsulfanyl)-2,5-dimethyl-hexenoic acid was preparedstarting from 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acidethyl ester (2.0 g, 6.4 mmol) dissolved in methanol (50 ml) and 10 NNaOH (20 ml). The resulting reaction mixture was worked up as outlinedin Example 1. Yield is 1.9 g, 99% of low melting solid. MS: 280 (M+H)⁺.

Starting from 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex4enoic acid(1;67 g, 5.8 mmol) and following the procedure as outlined in Example 1,1.5 g of 2-(4methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acidhydroxyamide was isolated as a colorless solid. mp 89° C.; Yield 94%;MS: 296 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 1.34 (s, 3H), 1.61 (s, 3H),1.74 (s, 3H), 2.41-2.58 (m, 2H), 3.80 (s, 3H), 5.17 (t, J=7.5 Hz, IH),6.86 (d, J=12.4 Hz, 2H), 7.35 (d, J=12.4 Hz, 2H).

EXAMPLE 4

N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-3-methyl-butyramide

2-(4-Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester wasprepared according to the general method of Example 1. Starting fromethyl 2-bromo-3-methyl-butanoate (20.9 g, 100 mmol) and4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of the product wasisolated. Yield 99%; Light yellow oil; MS: 271 (M+H)⁺.

2-(4-Methoxy-phenylsulfanyl)-3-methyl-butyric acid was prepared startingfrom 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester (5.8g, 21.6 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). Theresulting reaction mixture was worked up as outlined in Example 1. Yield5.0 g, 99%. Low melting solid. MS: 242 (M+H)⁺.

Starting from 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid (4.39g, 18.3 mmol) and following the procedure as outlined in Example 1, 1.5g of N-hydroxy-2-(4methoxy-phenylsulfanyl)-3-methyl-butyramide wasisolated as a colorless solid. mp 119° C.; Yield 33%; MS: 256 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆): δ 0.90-1.07 (m, 6H), 1.84-1.96 (m, 1H), 3.07 (d,J=8.8 Hz, 1H), 3.75 (s, 3H), 6.88 (d, J=15 Hz, 2H), 7.35 (d, J=15 Hz,2H).

EXAMPLE 5

N-Hydroxy-2-(4-methoxy-benzenesulfmyl)-2-methyl-3-phenyl-propionamide

N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide(400 mg, 1.26 mmol) (prepared in Example 1) was dissolved in methanol(100 ml) and 30% H₂O₂ (10 ml) was added. The reaction mixture wasstirred for 48 hours at room temperature at which time it was cooled to0° C. and quenched with saturated Na₂SO₃ (20 ml) solution. The reactionmixture became cloudy. It was stirred for 4 hours before it wasconcentrated in a room temperature water bath, diluted with water,extracted with CHCl₃ and washed with H₂O. The organic layer was driedover MgSO₄, filtered and concentted. The title compound was isolated bysilica gel column chromatography, eluting with 75% ethylacetate:hexane.Low melting solid. Yield: 220 mg (52%); MS: 334.1 (M+H)⁺; ¹H NMR (300Mz, CDCl₃): d 1.11 (s, 2H), 1.22 (s, 3H), 3.84 (s, 3H), 7.00-7.61 (m,9H).

EXAMPLE 6

2-(4-Methoxy-benzenesulfanyl)-2,5 dimethyl-hex-4-enoic acid hydroxyamide

Starting from 2-(4-methoxy-benzenesulfanyl)-2,5-dimethyl-hex-4-enoichydroxamide (900 mg, 3.0 mmol) (prepared in Example 3) and following theprocedure outlined in Example 5,2-(4-methoxy-benzenesulfmyl)-2,5dimethyl-hex-4-enoic acid hydroxyamidewas isolated as a colorless solid. Yield: 104 mg (10%); mp 108° C.; MS:312 (M+H)⁺; ¹H NMR (300 Mz, DMSO-d₆): δ 0.88 (s, 3H), 1.59 (s, 3H), 1.68(s, 3H), 2.27-2.80 (m, 2H), 5.02 (t, J=7.5 Hz, 1H), 7.09 (d, J=9 Hz,2H), 7.39 (d, J=9 Hz, 2H).

EXAMPLE 7

N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-3-methyl-butyramide

Starting from N-hydroxy-2-(4methoxy-phenylsulfanyl)-3-niethyl-butyramide(1 g, 3.9 mmol) as prepared in Example 4, and following the procedure ofExample 5, N-hydroxy-2-(4-methoxy-benzenesulfinyl)-3-methyl-butyramidewas isolated as a colorless solid. Yield: 420mg (40%); mp 163° C.; MS:272 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.89-1.12 (m, 6H), 1.63-1.74(m, 1H), 3.13 (d, J=7 Hz, 1H), 3.83 (s, 3H), 6.947.65 (m, 4H).

EXAMPLE 8

N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-2-phenyl-acetamide

Starting from N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide(240 mg, 0.83 mmol) as prepared in Example 2, and following theprocedure outlined in Example 5,N-hydroxy-2-(4-methoxy-benzenesulfinyl)-2-phenyl-acetamide was isolatedas colorless solid. Yield: 100 mg (40%); mp 135° C.; MS 304 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆): δ 3.75 (s, 3H), 4.38 (s, 1H), 6.92-7.69 (m, 9H)

EXAMPLE 9

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionarmide.

To a stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mmol) andanhydrous K₂CO₃ (10 gm, excess) in dry acetone (100 ml), α-bromo ethylacetate (3.3 gm, 20 mmol) was added in a round bottom flask and thereaction mixture was heated at reflux for 8 hours with good string. Atthe end, the reaction mixture was allowed to cool and the potassiumsalts were filtered off and the reaction mixture was concentrated. Theresidue was extracted with chloroform and washed with H₂O and 0.5 N NaOHsolution. The organic layer was further washed well with water, driedover MgSO₄, filtered and concentrated. (4methoxy-phenylsulfanyl)-aceticacid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g (100%);MS; 227 (M+H)⁺.

To a stirred solution of 60% 3-chloroperoxybenzoic acid (14.0 gm, 40mmol) in methylene chloride (100 ml) at 0° C.,(4methoxy-phenylsulfanyl)-acetic acid ethyl ester (4.4 g, 20 mmol) inCH₂Cl₂ (15 ml) was added slowly. The reaction mixture turned cloudy andwas stirred at room temperature for 6 hours. The reaction mixture wasthen diluted with hexanes (300 ml) and stirred for 15 minutes. Thesolids were fjitered off and Na₂SO₃ solution was added to the organiclayer which was stirred for at least 3 hours before the mixture wasextracted with CHCl₃ and washed with H₂O. The organic layer was driedover MgSO₄, filtered and concentrated and the colorless(4-methoxy-phenylsulfonyl)-acetic acid ethyl ester was isolated as anoil. Yield: 100%; MS: 259.1 (M+H)⁺.

To stirred solution of the (4-methoxy-benzenesulfonyl)-acetic acid ethylester (2.5 g, 10 mmol), benzyl bromide ( 1.8 gm, 10 mmol) and 18-Crown-6(500 mg) in acetone (250 ml) was added K₂CO₃ (10 gms, excess) and themixture was refluxed for 24 hours. At the end, the reaction mixture wasfiltered and the acetone layer was concentrated. The residue obtainedwas extracted with chloroform, washed well with water, dried overanhydrous MgSO₄, filtered and concentrated. The product obtained waspurified by silica-gel column chromatography, eluting with 30% ethylacetate: hexane. The product,2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester wasisolated as a low melting solid. Yield: 3.0 gm 86%; Low melting solid;MS: 349 (M+H)⁺.

To a stirred solution of2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (348mg, 1 mmol) in methanol (25 ml), 10 N NaOH (10 ml) was added. Thereaction mixture was stirred at room temperature for 48 hours. At theend, the reaction mixture was concentrated and carefully neutralizedwith dilute HCl. The residue obtained was extracted with chloroform,washed well with water, dried and concentrated The product obtained waspurified by silica-gel column chromatography by eluting with ethylacetate: methanol (95:5) to afford24-(methoxy-benzenesulfonyl)-3-phenyl-propionic acid as a colorless oil.Yield: 250 mg, 89%; MS: 321 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid (200mg, 0.625 mmol) and following the procedure as outlined in Example 1,150 mg of N-hydroxy-2-(4methoxy-benzenesulfonyl)-3-phenyl-propionamidewas isolated as a brown solid. Yield: 71 %; mp 180° C.; MS: 336 (M+H)⁺;¹H NMR (300 MHz, CDCl₃): δ 3.2 (m, 1H), 3.8 (s, 3H), 4.04.2 (m, 2H),7.0-8.0 (m, 9H).

EXAMPLE 10

2-(4-Methoxy-benzenesulfonyl)-hexanoic acid hydroxyamide

2-(4-Methoxy-phenylsulfanyl)-hexanoic acid ethyl ester was preparedaccording to the general method as outlined in Example 1. Starting fromethyl 2-bromo,hexanoate (7 g, 32 mmol) and 4-methoxybenzenethiol (4.2 g,30 mmol), 8.3 g of the product was isolated. Yield 98%; Light yellowoil; MS: 283 (M+H)⁺.

Starting from 2-(4-methoxy-phenylsulfanyl)-hexanoic acid ethyl ester.(2.8 g 10 mmol) and following the procedure as outlined in Example 9, 3g of 2-(4methoxy-benzenesulfonyl)-hexanoic acid ethyl ester was isolatedas a colorless solid. Yield: 95%; mp 62° C.; MS: 314 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester (2g, 6.3 mmol) 1.5 g (83%) of 2-(4-methoxy-benzenesulfonyl)-hexanoic acidwas isolated as a colorless solid by following the procedure as outlinedin Example 9. Mp 116° C.; MS: 287 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-hexanoic acid (1.0 g, 3.1mmol) and following the procedure as outlined in Example 1, 700 mg of2-(4medioxy-benzenesulfonyl)-hexanoic acid hydroxyamide was isolated asa colorless solid. Yield: 60%; mp 130° C.; MS: 302 (M+H)⁺; ¹H NMR (300MHz, CDCl₃): δ 0.786 (t, J=7.2 Hz, 3H), 1.1-1.3 (m, 411), 1.6-1.8 (m,2H), 3.7 (m, 1H), 3.9 (s, 3H),7.2 (d, J=11 Hz, 2H), 7.8 (d, J=11 Hz,2H), 9.3 (s, 1H), 10.9 (s, 1H).

EXAMPLE 11

2-(4-Methoxy-benzene sulfonyl)-tetradecanoic hydroxyamide

2-(4-Methoxy-phenylsulfanyl)-tetradecanoic acid ethyl ester was preparedaccording to the general method as outlined in Example 1. Starting fromthe corresponding ethyl -2-bromomyristate (5.0 g, 14.9 mmol) and4-methoxythiophenol (1.9 g, 13.4 mmol), 5.0 g of the product wasisolated. Yield 98%; Light yellow oil; MS: 393 (M+H)⁺.

Starting from 2-(4-methoxy-phenylsulfanyl)-tetradecanoic acid ethylester. (3.9 g 10 mmol) and following the procedure as outlined inExample 9, 3.2 g of 2-(4methoxy-benzenesulfonyl)-tetradecanoic acidethyl ester was isolated as a colorless solid. yield: 76%; Oil; MS: 425(M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-tetradecanoic acid ethylester (2.5 g, 5.9 mmol), 2.0 g (85%) of2-(4-methoxy-benzenesulfonyl)-tetradecanoic acid was isolated as acolorless solid by following the procedure as outlined in Example 9. mp82 ° C; MS: 397 (M+H)⁺.

Starting from 2-(4-methoxy-benzene sulfonyl)-tetradecanoic acid (1.14 g,2.9 mmol) and following the procedure as outlined in Example 1, 670 mgof 2-(4-methoxy-benzenesulfonyl)-tetradecanoic hydroxyamide was isolatedas an off-white solid Yiefld: 57%; mp 114° C.; MS: 414 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆): δ 0.85 (t, J=7 Hz, 3H), 1.16-1.27 (m, 20 H), 1.66(m, 2H), 3.62-3.70 (m, 1H), 3.87 (s, 3H), 7.12 (d, J=15 Hz, 2H), 7.73(d, J=15 Hz, 2H).

EXAMPLE 12

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionamide

To a stirred solution of 2-(4methoxy-benzenesulfonyl)-3-phenyl-propionicacid ethyl ester (1.0 gm, 3mmol) (example 9), methyl iodide (1 ml,excess) and 18-Crown-6 (500 mg) in acetone (250 ml), K₂CO₃ (10 gm,excess) was added and the reaction mixture was refluxed for 24 hours. Atthe end, the reaction mixture was filtered and the acetone layer wasconcentrated The residue obtained was extracted with chloroform, washedwell with water, dried over anhydrous MgSO₄, filtered and concentratedThe product obtained was purified by silica-gel column chromatography byeluting it with 30% ethyl acetate:hexanes to afford2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid ethylester as a colorless oil. Yield 1.0 g, 98%; MS: 349 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionicacid ethyl ester (900 mg, 2.7 mmol), 850 mg (quantitative) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid wasisolated by following the procedure as outlined in Example 9. Colorlessoil, MS 335 (M+H)⁺.

Staring from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionicacid (900 mg, 2.7 mmol) and following the procedure as outlined inExample 1, 450 mg ofN-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionamidewas isolated as a brown solid. Yield: 48%; mp 58° C.; MS: 350 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 8 1.4 (s, 3H), 3.1 (d, J=9 Hz, 1H), 3.6 (d, J=9Hz, 1H), 3.9 (s, 3H), 6.8-7.8 (m, 9H).

EXAMPLE 13

2-(4-Methoxy-benzenesulfonyl)-2,5-dinethyl-hex-4-enoic acid hydroxyamide

Starting from 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester(Example 1) (12 g; 50 mmol) and following the procedure as outlined inExample 9, 12 g of 2-(4methoxy-benzenesulfonyl)-propionic acid ethylester was isolated as a semi-solid. yield 100%; MS: 256.1 (M+H)⁺.

Following the procedure as outlined in Example 12,2-(4-methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid ethyl esterwas prepared, starring from (1 g, 3.6 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and isoprenylbromide (1.0 g, 6 mmol). Yield 1.0 g, 81%; Colorless oil; MS: 341(M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2,5-dimethyl-hexenoic acidethyl ester (900 mg, 2.6 mmol) 800 mg (96%) of2-(4-methoxybenzenesulfonyl)-2,5-dimethyl-hexenoic acid was isolated asa semi solid by following the procedure as outlined in Example 9. MS:313 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2,5dethyI-hex4noic acid (1.0g, 3.2 mmol) and following the procedure as outlined in Example 1, 700mg of 2-(4-methoxy-benzenesulfonyl)-2,5dimethyl-hex-4-enoic acidhydroxyamide was isolated as a low melting solid. Yield: 67%; MS: 328(M+H)⁺; ¹H NMR (300 Mz, CDCl₃): δ 1.3 (s, 3H), 1.5 (d, J=6.2 Hz, 6H),2.5-3.0 (m, 2H), 3.9 (s, 3H), 7.0 (d, J=11 Hz, 2H), 7.8 (d, J=11 Hz,2H).

EXAMPLE 14

3-(Biphenyl-4-yl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide

Following the procedure as outlined in Example 12,3-(biphenyltyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acidethyl ester was prepared, starting from (2.7 g,10 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and 4(chloromethyl)biphenyl (2.5 g, 12 mmol). Yield 4.0 g, 91%; Colorlessoil; MS: 438 (M+H)⁺.

Starting from 3-(biphenyl-4-yl)-2-(4-methoxy-benzenesulfonyl)-2-methylpropionic acid ethyl ester (3 g, 6.8 mmol), 2.5 g (89%) of3-(biphenylfyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl propionic acidwas isolated as a colorless solid by following the procedure as outlinedinExample9. mp 161° C.; MS: 411 (M+H)⁺.

Starting from3-(biphenyl-4-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid(2.0 g, 4.8 mmol) and foluowing the procedure as outlined in Example 1,1.2 g of3-(biphenyl-4-yl)-N-hydroxy-2-(methoxy-benzenesulfonyl)-2-methyl-propionamidewas isolated as colorless solid. Yield: 58%; mp 177° C.; MS: 426 (M+H)⁺;¹H NMR (300 MHz, CDCl₃): δ 1.4 (s, 3H), 3.2 (d, J=9 Hz, 1H), 3.7 (d, J=9Hz, 1H), 3.9 (s, 3H), 7.0 -7.8 (m, 13H), 9.7 (bs, 1H).

EXAMPLE 15

2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-dienoic acidhydroxyamide

Following the procedure as outlined in Example 12,2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-dienoic acidethyl ester was prepared, starting from (2.7 g, 10 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and geranylbromide (3.0 g, 13 mmol). Yield 4.0 g, 98%; Colorless oil; MS: 409(M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-dienoic acidethyl ester (3 g, 7.4 mmol), 2.8 g (96%) of2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-dienoic acid wasisolated as a colorless oil by following the procedure as outlined inExample 9. MS: 379 (M−H)⁻.

Starting from2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-enoic acid (2.0g, 5.2 mmol) and following the procedure as outlined in Example 1, 1.8 gof 2-(4-methoxy-benzenesulfonyl)2,5,9-timethyl-deca-4,8-enoic acidhydroxyamide was isolated as a colorless oil. Yield: 88%; MS: 396(M+H)⁺; ¹H NMR (300 Mz, CDCl₃): δ 1.4 (s, 3H), 1.6 (s, 3H), 1.65 (s,3H), 1.7 (s, 3H), 2.0-3.1 (m,6 H), 3.9 (s, 3H), 5.5 (m, 2H), 6.98 (d,J=9.0 Hz, 2H), 7.7 (d, J=9.0 Hz, 2H).

EXAMPLE 16

3-Cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide

Following the procedure as outlined in Example 12,3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid ethylester was prepared, starting from (2.7 g, 10 mmol) of2-(4-medioxy-benzenesulfonyl)-propionic acid ethyl ester andbromomethylcyclohexane (1.8 g, 10 mmol). Yield 3.5 g, 95%; Yellow oil;MS: 369 (M+H)⁺.

Starting from 3cyclohexyl-2-(4-methoxy-benzenesulfonyl-2-methylpropionic acid ethyl ester (3 g, 8.1 mmol) 2.5 g (90%) of3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methyl propionic acid wasisolated as colorless solid by following the procedure as outlined inExample 9. mp 116° C.; MS: 341 (M+H)⁺.

Starting from3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid (2.0g, 5.8 mmol) and following the procedure as outlined in Example 1, 1.1 gof3-cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamidewas isolated as colorless solid. Yield: 55%; mp 58° C.; MS: 356 (M+H)⁺;¹H NMR (300 MHz, CDCl₃) δ 1.4 (s, 3H), 2.3-1.0 (m, 13 H), 3.9 (s, 3H),7.0 (d, 8.8 Hz, 2H), 7.69 (d, 9.0 Hz, 2H).

EXAMPLE 17

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperdin-1-yl-ethoxy)-Phenyl]-propionamide

Following the procedure as outlined in example 12,24methoxy-benzenesulfonyl)-2-methyl3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid ethyl ester wasprepared, starting from (2.7 g, 10 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the4-(2-piperidin-1-yl-ethoxy)-benzyl chloride (2.9 g, 10 mmol). Yield 4.8g, 98%; Brown oil; MS: 490 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester (4.0 gm, 7.9 mmol) 3.5 g (Yield: 94%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid was isolated as colorless crystals by following the procedure asoutlined in example 9. Mp 106° C.; MS: 462.5 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid (2.0 g, 4.2 mmol) and following the procedure as outlined inexample 1, 1 g ofN-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionamidewas isolated as colorless solid. Yield: 1 g, 48%; mp 98° C.; MS: 477(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 1.2 (s, 3H), 3.5-1.5 (m, 16 H), 3.9(s, 3H), 4.4 (m, 1H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 18

2-4-(2-Azepan-1-yl-ethoxy)-benzyl)-2-(4methoxy-benzenesulfonyl)-propionicacid hydroxyamide

Following the procedure as outlined in example 12,2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionicacid ethyl ester was prepared, starting from (2.7 g, 10 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the1-[2-(4-chloromethyl-phenoxy)ethyl]-azepane (3.03 g, 10 mmol). Yield 4.5g, 90%; Brown oil; MS: 504 (M+H)⁺.

Starting from2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionicacid ethyl ester (4.0 gm, 7.9 mmol) 3.5 g (Yield: 94 %) of2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionicacid was isolated as semi-solid by following the procedure as outlinedin example 9. MS: 476 (M+H)⁺.

Starting from2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionicacid (2.0 g, 4.2 mmol) and following the procedure as outlined inexample 1, 1 g of2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)propionicacid hydroxyamide was isolated as colorless solid. Yield: 1.8 g, 87%; mp68° C.; MS: 491 (M+H)⁺; 1H NMR (300 MDz, CDCl₃): δ 1.23 (s, 3H), 3.5-1.7(m, 18 H), 3.8 (s, 3H), 4.2 (m, 1H), 6.4 -7.89 (m, 8H), 10.9 (bs, 1H).

EXAMPLE 19

2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4methoxy-benzenesulfonyl)-pentanoicacid hydroxyamide

2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoicacid ethyl ester was prepared according to the general method asoutlined in example 12. Starting from2-(4-methoxy-benzenesulfonyl)-pentanoic acid ethyl ester (3.5 g, 11.7mmol) and 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane (3.9 g, 12.8mmol). Yield 2.58 g (42%); brown oil; MS: 532.4 (M+H)⁺.

2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzetesulfonyl)-pentanoicacid was prepared starting from2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoicacid ethyl ester (2 g, 3.76 mmol) dissolved in methanol (300 ml) and 10N NaOH (15 ml). The resulting mixture was worked up as outlined inexample 1. Yield 830 mg (44%); brown solid; mp 55° C.; MS: 504.4 (M+H)⁺.

Starting from2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoicacid (690 mg, 1.37 mmol) and following the procedure as outlined inexample 1, 240 mg of2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoicacid hydroxyamide was isolated as a yellow solid. Yield 34%; mp 85° C.;MS: 519.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.71 (t, J=7.3 Hz, 31),0.78-1.77 (m, 16 H), 3.04-3.46 (m, 4H), 3.87 (s, 3H), 4.26 (m, 2H) 6.87(d, J=8.7 Hz, 2H), 7.14 (m, 4H), 7.71 (d, J=9 Hz, 2H), 9.07 (s, 1H), 10(s, 1H).

EXAMPLE 20

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methy-3-[4-(2-N,N-diisopropylamino-ethoxy)-phenyl]-propionamide

Following the procedure as outlined in example 12,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-iisopropylanino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, startingfrom (5.4 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acidethyl ester and the 4-(2-N,N diisopropyl amino-ethoxy)-benzyl chloride(6.1 g, 20 mmol). Yield 8.9 g, 88%; Yellow oil; MS: 506.5 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropylamino-ethoxy)-phenyl]-propionic acid ethyl ester (4.0 gm, 7.9 mmol) 3.5g (Yield: 92%) of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,Ndiisopropyl amino-ethoxy)-phenyl]-propionic acid was isolated ascolorless crystals by following the procedure as outlined in example 9.Mp 68° C.; MS: 478.6 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropylamino-ethoxy)-phenyl]-propionic acid (2.0 g, 4.1 mmol) and following theprocedure as outlined in example 1, 1 g of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropylamino-ethoxy)-phenyl]-propionamide was isolated as colorless solid.Yield: 1 g, 49%; mp 98° C., (Hcl Salt); MS: 493 (M+H)⁺; ¹H NMR (300 MHz,CDCl₃): δ 1.2 (s, 3H), 1.3 (d,6H), 1.4 (d,6H), 3.5-1.5 (m, 6 H), 3.9 (s,3H), 4.4 (s, 2H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 21

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionamide

Following the procedure as outlined in example 12,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, startingfrom (5.4 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acidethyl ester and the 4-(2-N,N-diethyl amino-ethoxy)-benzyl chloride (5.5g, 20 mnmol). Yield 8.5 g, 89%; Brown oil; MS: 478.6 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester (3.5 gm, 7.7 mmol) 3.0g (Yield: 85%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid was isolated as colorless crystalsby following the procedure as outlined in example 9. Mp 96-98° C.; MS:450.5 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid (2.0 g, 4.4 mmol) and following theprocedure as outlined in example 1, 1 g of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N ethylamino-ethoxy)-phenyl]-propionamide was isolated as colorless solid.Yield: 1 g, 48%; mp 56-59° C. (HCl Salt); MS: 465.5 (M+H)⁺; ¹H NMR (300MHz, CDCl₃): δ 1.1 (t, 6H), 1.3 (s,3H), 3.2-3.9 (mn, 8 H), 3.9 (s, 3H),4.3 (s, 2H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 22

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionamide

Following the procedure as outlined in example 12,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester was prepared, starting from (5.2 g, 20 mmol) of2-(4-methoxy-benzenesulfonyl)-propidnic acid ethyl ester and the3-(2-piperidin-1-yl-ethoxy)-benzyl chloride (6.0 g, 20 mmol). Yield 8.2g, 83%; Brown oil; MS: 490 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester (6.0 gm, 12.2 mmol) 4.9 g (Yield: 79%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid was isolated as colorless crystals by following the procedure asoutlined in example 9. Mp 112 ° C.; MS: 462.5 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid (3.0 g, 6.5 mmol) and following the procedure as outlined inexample 1, 1.8 g of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionamidewas isolated as colorless solid. Yield: 1.8 g, 58%; mp 74° C.; MS: 477(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 1.25 (s, 3H), 1.6-1.8 (m, 6 H),2.5-3.7 (m, 8H), 3.9 (s, 3H), 4.4 (t, 2H), 6.7-7.8 (m, 8H), 10.8 (bs,1H).

EXAMPLE 23

3-(4-{3-[4-(3-Chloro-phenyl)-piperain-1-yl]-propoxy}-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide

Following the procedure as outlined in example 12,3-(4-{3-[4-(3-chlorophenyl)-piperazin-1-yl]-propoxy}-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionicacid ethyl ester was prepared, starting from (2.72 g, 10 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the1-[2-(4-chloromethyl-phenoxy)-ethyl]4-(3-chlorophenyl)-piperazine (4.2g, 11 mmol). Yield 5.5 g, 89%; Brown oil; MS: 616 (M+H)⁺.

Starting from3-(4-{3-[4-(3-chloro-phenyl)-piperazin-1-yl]-propoxy}-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionicacid ethyl ester (4.0 gm, 6.5 mmol) 3.0 g (Yield: 78%) of3-(4-{3-[4-(3-chloro-phenyl)-piperazin-1-yl]-propoxy}-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid was isolated as colorless crystalsby following the procedure as outlined in example 9. Mp 196° C.; MS:588.1 (M+H)⁺.

Starting from3-(4-{3-[4-(3-chloro-phenyl)-piperazin-1-yl]-propoxy}-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionicacid (3.0 g, 5.1 mmol) and following the procedure as outlined inexample 1, 1.8 g of3-(4-{3-[4-(3-chloro-phenyl)-piperazin-1-yl]-propoxy}-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionanudewas isolated as pale yellow solid. Yield: 1.8 g, 55%; mp 122° C. (HClSalt); MS: 640 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 1.2 (s, 3H), 3.4-1.5(m, 14 H), 3.9 (s, 3H), 4.5 (m, 2H), 6.5-8.2 (m, 12H), 10.3 (bs, 1H).

EXAMPLE 24

2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholinlyl-ethoxy)-benzyl]-hex-4-enoicacid hydroxyamide

To a stirred solution of (4-methoxy-benzenesulfonyl)-acetic acid ethylester (5.16 g, 20 mmol), isoprenyl bromide (3.0 g, 20 mmol) and18-Crown-6 (500 mg) in acetone (250 ml) was added K2CO3 (10 gms, excess)and the mixture refluxed foe 24 hours. At the end, the reaction mixturewas filtered and the acetone layer was concentrated. The residueobtained was extracted with chloroform, washed well with water, driedover anhydrous MgSO4, filtered and concentrated. The product obtainedwas purified by silica-gel column chromatography, eluting with 30% ethyacetate: hexane. The product2-(4methoxy-benzenesulfonyl)-5-methyl-hex-4-enoic acid ethyl ester wasisolated as a colourless oil. Yield: 3.0 g, 93%.

Following the procedure as outlined in example 12,2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-hextenoicacid ethyl ester was prepared, starting from (3.26 g, 10 mmol) of2-(4-methoxy-benzenesulfonyl)-5-methyl-hex-4-enoic acid ethyl ester and4-(2-morpholin-1-yl-ethoxy)-benzyl chloride (3.0 g, 11 mmol). Yield 4.5g, 82%; Brown oil; MS: 546 (M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-hex-4-enoicacid ethyl ester (3.0 gm, 5.5 mmol) 2.1 g (Yield: 75%) of2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl-etoxy)-benzyl]-hex-4-enoicacid was isolated as semi-solid by following the procedure as outlinedin example 9. MS: 518.6 (M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-hex-4-enoicacid (1.0 g, 1.9 mmol) and following the procedure as outlined inexample 1, 450 mg of2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-hex-4-noicacid hydroxyamide was isolated as pale yellow solid. Yield: 450 mg, 45%;mp 92° C. (HCl Salt); MS: 570 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 1.3 (d,3H), 1.65 (d, 2H), 3.5-1.8 (m, 14 H), 3.9 (s, 3H), 4.5 (m, 2H), 5.4 (m,1H), 6.5-7.9 (m, 8H), 11.5 (bs, 1H).

EXAMPLE 25

N-Hydroxy-2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionamide

To a stirred solution of 4-hydroxy thiophenol (12.6 g, 100 mmnol) andtriethyl amine (15.0 g, 150 mmol) in chloroform (400 ml) 2-bromoethyipropionate (18. 2 g, 100 mmol) was added drop wise. The reactionmixture was refluxed for 1 hr and cooled to room temperature. Thereaction mixture was washed with water, dried and concentrated.2-(4-hydroxy-phenylsulfanyl)-propionic acid ethyl ester was isolated ascolorless oil. Yield: 22.0 g, 99%, MS: 227 (M+H).

To stirred solution of 2-(4-hydroxy-phenylsulfanyl)-propionic acid ethylester (11.3 g, 50 mmol), and K₂CO₃ (50 g, excess) in acetone (300 ml)ethyl iodide (20 ml, excess) was added and refluxed for 8 hrs. At theend, reaction mixture was filtered and concentrated The residue obtainedwas extracted with chloroform and washed well with water. It was driedand concentrared. The product, 2-(4-ethoxy-phenylsulfanyl)-propionicacid ethyl ester was isolated as colorless oil. Yield: 12.0 g, 98%; MS:255 (M+H).

2-(4-Ethoxy-phenylsulfanyl)-propionic acid ethyl ester was converted to2-(4-ethoxy-phenylsulfonyl)-propionic acid ethyl ester by following theprocedure as described in example 9, paragraph 2.

Following the procedure as outlined in example 12,2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, startingfrom (3.5 g, 12.2 mmol) of 2-(4-ethoxy-benzenesulfonyl)-propioni( acidethyl ester and the 4-(2-N,N-diethyl amino-ethoxy)-benzyl chloride (3.5g, 12.2 mnmol). Yield 4.8 g, 80%; Brown oil; MS: 492.6 (M+H)⁺.

Starting from 2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester (4.0 gm, 8.1 mmol) 3.2g (Yield: 80%) of2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid was isolated as colorlesssemi-solid by following the procedure as outlined in example 9. MS:464.5 (M+H)⁺.

Starting from 2-[4-ethoxy-benzenesulfonyl)-2-methyl-3-(4-(2-N,N-diethylamino-ethoxy)-phenyI]-propionic acid (2.0 g, 4.3 mmol) and following theprocedure as outlined in example 1, 1.2 g of2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,Niethylamino-ethoxy)-phenyl]-propionamide was isolated as colorless low meltingsolid. Yield: 1.2 g 57%; (HCl Salt); MS: 478.5 (M+H)⁺; ¹H NMR (300 MHz,CDCl₃): δ 0.9 (t, 3H), 1.1 (t, 6H), 1.3 (s,3H), 3.2-3.9 (m, 8 H), 3.9(s, 3H), 4.3 (s, 2H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 26

(4E)-2-(4-Methoxy-benzenesulfonyl)-5,9ethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-deca-4,8-dienoic acid hydroxyamide

To a stirred solution of (4-methoxy-benzenesulfonyl)-acetic acid ethylester (5.16 g, 20 mmol), geranyl bromide (4.2g, 20 mmol) and 18-Crown-6(500 mg) in acetone (250 ml) was added K2CO3 (10 gms, excess) and themixture refluxed foe 24 hours. At the end, the reaction mixture wasfiltered and the acetone layer was concentrated. The residue obtainedwas extracted with chloroform, washed well with water, dried overanhydrous MgSO₄, filtered and concentrated. The product obtained waspurified by silica-gel column chromatography, eluting with 30% ethyacetate: hexane. The product2-(4-methoxy-benzenesulfonyl)-5,9-dimethyl-deca-4,8-dienoic acid ethylester was isolated as a colourless oil. Yield: 7.0 g,89%.

Following the procedure as outlined in example 12,2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-deca-4,8-dienoicacid ethyl ester was prepared, starting from (1.0 g, 2.5 mmol) of2-(4-methoxy-benzenesulfonyl)-5,9-dimethyl-deca-4,8-dienoic acid ethylester and 4-(2-morpholin-1-yl-ethoxy)-benzyl chloride (800 mg, 2.5mmol). Yield 1.2 g, 76%; Brown oil; MS: 614 (M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4yl-ethoxy)-benzyl]-deca-4,8-dienoicacid ethyl ester (2.0 gm, 3.2 mmol) 1.5 g (Yield: 80%) of2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-deca-4,8-dienoicacid was isolated as semi-solid by following the procedure as outlinedin example 9. MS: 586.6 (M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-deca-4,8-dienoicacid (1.0 g, 1.7 mmol) and following the procedure as outlined inexample 1, 550 mg of(4E)-2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4(2-morpholin-4-yl-ethoxy)-benzyl]-deca-4,8-dienoicacid hydroxyamide was isolated as pale yellow solid. Yield: 550 mg, 53%;mp 61° C. (HCl Salt); MS: 638 (M+H)⁺.

EXAMPLE 27

2-[4-(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoicacid hydroxyamide

2-[4-(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoicacid ethyl ester was prepared according to the general method asoutlined in example 12. Starting from2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester (4 g, 12.7 mmol)and [2-(4-chloromethyl-phenoxy)-ethyl]diethylamine (3.38 g, 14 mmol).Yield 8.21 g crude (100%); brown oil; MS: 520.4 (M+H)⁺.

2-[4-(2-Diethylamino-ethoxy)benzyl]-2-(methoxy-benzenesulfonyl)-hexanoicacid was prepared starting from2-[4-(2-ethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoicacid ethyl ester (8 g, 15.4 mmol) dissolved in methanol (200 ml) and 10N NaOH (30 ml). The resulting mixture was worked up as outlined inexample 1. Yield 3.88 g crude (51%); brown oil; MS: 492 (M+H)⁺.

Starting from2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoicacid (3.88 g, 7.89 mmol) and following the procedure as outlined inexample 1, 800 mg of2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoicacid hydroxyamide was isolated as a yellow powder. Yield 20%; mp 67° C.;MS: 507.4 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.75 (t, J=7.1 Hz, 3H),1.05 (m, 2 H), 1.23 (t, J=7.2 Hz, 6H) 1.37-1.91 (m, 2H), 3.13 (m, 4H),3.38-3.51 (m, 4H), 3.87 (s, 3H), 4.3 (t, J=4.8 Hz, 2H), 6.88 (d, J=8.7Hz, 2H), 7.15 (m, 4H), 7.7 (d, J=9 Hz, 2H), 9.07 (s, 1H), 10.1 (s, 1H)

EXAMPLE 28

N-Hydroxy-2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4(2-piperidin-1-yl-ethoxy)-phenyl]-propionamide

Following the procedure as outlined in example 12,2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester was prepared, starting from (3.1 g, 10 mmol) of2-(4-n-butoxy-benzenesulfonyl)-propionic acid ethyl ester (Prepared from2-(4-hydroxy-phenylsulfanyl)-propionic acid ethyl ester andn-butylbromide following the procedure outlined in example 27 )the4-(2-piperidin-1-yl-ethoxy)-benzyl chloride (3.0 g, 10.1 mmol). Yield4.5 g, 84%; Brown oil; MS: 532.7 (M+H)⁺.

Starting from2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester (5.0 gm, 9.4 mmol) 4.2 g (Yield: 88%) of2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid was isolated as colorless solid by following the procedure asoutlined in example 9. MS: 504.6 (M+H)⁺

Starting from2-(4n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid (3.0 g, 5.9 mmol) and following the procedure as outlined inexample 1, 1.3 g of2-(4n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionamidewas isolated as colorless solid. MP. 65 C, Yield: 1.3 g, 42%; (HClSalt); MS: 478.5 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 0.9 (t, 3H), 1.2 (s,3H), 1.3-1.9 (m,10H), 2.8-4.5 (m, 12 H),, 6.8-7.8 (m, 8H), 10.8 (bs,1H).

EXAMPLE 29

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethylamino-ethoxy)-phenyl]-propionamide

Following the procedure as outlined in example 12,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, startingfrom (5.0 g, 18 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acidethyl ester and the 3-(2-N,N-diethyl amino-ethoxy)-benzyl chloride (4.9g, 18 mnmol). Yield 8.1 g, 93%; Brown oil; MS: 478.1 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester (8.1 gm, 16.9 mmol) 6.7g (Yield: 88%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid was isolated as colorlesssemi-solid by following the procedure as outlined in example 9. MP:78-81; MS: 450.1 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid (6.7 g, 15 mmol) and following theprocedure as outlined in example 1, 1.5 g of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-NN-diethylamino-ethoxy)-phenyl]-propionamide was isolated as colorless low meltingsolid. Yield: 1.5 g, 21%; (HCl Salt); MS: 450.5 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆): δ 1.21 (t, 6Hi), 1.26 (s, 3H), 3.18-3.24 (m, 2H), 3.38 (m,4H), 3.43-3.46 (m, 2H), 3.80 (s, 3H), 4.30 (s,2H), 6.76-6.78 d, 2H),6.84-_(7.2) (m,6H), 10.3 (bs, 1H).

EXAMPLE 30

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionamide

Following the procedure as outlined in example 12,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester was prepared, starting from (5.2 g, 20 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the3-(2-morpholin-1-yl-ethoxy)-benzyl chloride (6.0 g, 20 mmol). Yield 9.1g, 93%; Brown oil; MS: 492 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester (10.0 gm, 20.3 mmol) 8.0 g (Yield: 86%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionicacid was isolated as colorless crystals by following the procedure asoutlined in example 9.; MS: 464.5 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionicacid (4.55 g, 9.8 mmol) and following the procedure as outlined inexample 1, 440 mg of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholi-1-yl-ethoxy)-phenyl]-propionamide was isolated as colorless solid.Yield: 440 mg, 9%; mp 63° C.; MS: 479.5 (M+H)⁺; ¹H NMR (300 Mhz,DMSO-d₆): δ 1.26 (s, 3H), 3.18-3.8 (m, 12H), 3.9 (s, 3H), 4.4 (m, 2H),6.7-8.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 31

6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoic acid hydroxyamide

Following the procedure as outlined in Example 9,6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoicacid ethyl ester was prepared, starting from (5.0 g, 20 mmol) of2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 4-phathalimidobromobutane (5.66 g, 20 mmol). Yield 8.4 g, 97%; Colorless oil; MS: 474(M+H).

Starting from6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4methoxy-benzenesulfonyl)-2-methyl-hexanoicacid ethyl ester (8.4 g, 17.7 mmol) 6.95 g (88%) of6-(1,3-Dioxo-1,3-dihydro-isindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoicacid was isolated as colorless oil by following the procedure asoutlined in Example 9. MS: 446 (M−H)⁻.

Starting from6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoicacid (4.9 g, 11 mmol) and following the procedure as outlined in Example1, 3.1 g of 6-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl -hexanoic acidhydroxyamide was isolated as a light brown solid; Yield: 46%; mp146-148° C.; MS: 461.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.55 (s,3H), 1.61-3.77 (m, 8H), 3.82 (s, 3H), 6.92-8.21 (m, 8H), 10.70 (bs,1H),11.20 (bs,1H).

EXAMPLE 32

3-[4-(2-Diethylamino-ethoxy)-phenyl]-2-(4-furan-2-yl-benzenesulfonyl)-N-hydroxy-2-methyl-propionamide

To a stirred solution of 4-bromo thiophenol (19.0 g, 100 mmol) andtriethyl amine (15.0 g, 150 mmol) in chloroform (400 ml) 2-bromoethylpropionate (18. 2 g, 100 mmol) was added drop wise. The reactionmixture was refluxed for 1 hr and cooled to room temperature. Thereaction mixture was washed with water, dried and concentrated.2-(4-bromo-phenylsulfanyl)-propionic acid ethyl ester was isolated ascolorless oil. Yield: 28.0 g, 99%, MS: 290 (M+H).

2-(4-bromo-phenylsulfanyl)-propionic acid ethyl ester was converted to2-(4-bromo-phenylsulfonyl)-propionic acid ethyl ester by following theprocedure as described in example 9, paragraph 2.

A mixture of 2-(4-bromo-phenylsulfonyl)-propionic acid ethyl ester (6.4g, 20 mmol), 2-(tributyl stannyl)furan (7.5g, 21 mmol) and (Ph₃P)₄Pd(500 mg) was refluxed in degassed tolune (250 ml) for 8 hrs. At the endreaction rnixture was filtered through Celite and concentrated. Theproduct was purified by silica gel column chromatography by eluting itwith 50% ethylacetate : hexane. Colorless oil. Yield: 5.9 g, 95%, MS:309 (M+H).

Following the procedure as outlined in example 12,2-(4-(2-furanyl-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, startingfrom (3.08 g, 10.0 mmol) of 2-(4-(2-furanyl-benzenesulfonyl)-propionicacid ethyl ester and the 4-(2-N,N-diethyl aminoethoxy)-benzyl chloride(3.5 g, 12.2 mmol). Yield 5.0 g, 97%; Brown oil; MS: 514.6 (M+H)⁺.

Starting from 2-(4-(2-furanyl-benzenesulfonyl)-2-methyl-3-[4-(2-N,Nethylaminothoxy)-phenyl]-propionic acid ethyl ester (5.1 gm, 10.0 mmol) 3.8 g(Yield: 78 %) of2-(4-(2-furanyl-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid was isolated as colorless solid byfollowing the procedure as outlined in example 9. MP: 58 C, MS: 486.5(M+H)⁺.

Starting from2-(4-(2-furanyl-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid (5.0 g, 10.3 mmol) and followingthe procedure as outlined in example 1, 1.2 g of2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-ethylaminoethoxy)-phenyl]-propionamide was isolated as colorless low meltingsolid. Yield. 3.2 g, 62%; (HCl Salt); MS: 502 (M+H)⁺; ¹H NMR (300 MHz,CDCl₃): δ 1.23 (t, 6H), 1.4 (s, 2H), 2.8 (q,4H), 3.0 (t, 2 H), 4.1 (t,2H), 6.5-8.0 (m, 7H).

EXAMPLE 33

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-butyramide

2-(4-Methoxy-phenylsulfanyl)-butyric acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting fromethyl 2-bromobutyrate (10.71 g, 55 mmol) and methoxythiophenol (7 g, 50mmol), 5.19 g (40%); clear oil; MS: 255.2 (M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-butyric acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting from2-(4-methoxy-phenylsulfanyl)-butyric acid ethyl ester (5 g, 20 mmol).Yield 5.74 g (100%); clear oil; MS: 287.1 (M+H)⁺.

Following the procedure as outlined in example 12,2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-butyricacid ethyl ester was prepared, starting from (3.5 g, 12.2 mmol) of2-(4-methoxy-benzenesulfonyl)-butyric acid ethyl ester and the4-[2-(chloromethyl-phenoxy)-ethyl]-morpholine (2.34 g, 6.7 mmol). Yield5.7 g, 100%; Brown oil; MS: 506.4 (M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholinyl-ethoxy)-benzyl]-buticacid ethyl ester (5.54 gm, 11 mmol) 2.9 g (Yield: 55%) of2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-butyricacid was isolated as colorless semi-solid by following the procedure asoutlined in example 9. MS: 478.3 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yloxy)-benzyl]-butyric acid (2.6 g, 5.4 mmol) and following the procedureas outlined in example 1, 510 mg ofN-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-butyramidewas isolated as a brown solid. Yield 2%; mp 51° C.; MS: 493.3 (M+H)+; ¹HNMR (300 MHz, DMSO-d₆): δ 0.90 (t, J=7.2 Hz, 3H), 1.69-1.96 (m, 4 H),2.67 (t, 2H), 3.34 (m, 8H), 3.87 (s, 3H), 4.04 (m, 2H) 6.8 (d, J=8.7 Hz,2H), 7.14 (m, 4IH), 7.73 (d, J=4.7 Hz, 2H), 9.08 (s, 1H), 10.8 (s, 1H).

EXAMPLE 34

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butyramide

Following the procedure as outlined in example 12,2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butyricacid ethyl ester was prepared, starting from (1.0 g, 3.33 mmol) of2-(4-methoxy-benzenesulfonyl)-butyric acid ethyl ester and the1-[2-(4-chloromethyl-phenoxy)-ethyl]-piperidine (0.85 g, 3.36 =mol).Yield 1.07 g, 62%; Brown oil; MS: 504.4 (M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butyricacid ethyl ester (3.7 gm, 7.3 mmol) 2.2 g (Yield: 63 %) of2-(4-Methoxy-benzenesulfonyl)-2-[(2-piperidin-1-yl-ethoxy)-benzyl]-butyric acid was isolated as colorless semi-solid byfollowing the procedure as outlined in example 9. MS: 476( M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butyricacid (2.2 g, 4.63 mmol) and following the procedure as outlined inexample 1, 360 mg ofN-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butyramidewas isolated as a brown solid. Yield 16%; mp 75° C.; MS: 491.3 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆): δ 0.90 (t, J=7.1 Hz, 3H), 1.36-1.96 (m, 4 H),2.4-2.63 (m, 14H), 3.87 (s, 3H), 4.01 (t, J=5.9 Hz, 2H) 6.8 (d, J=8.5Hz, 2H), 7.11 (m, 4H), 7.71 (d, J=8.8 Hz, 2H), 9.09 (s, 1H), 10.8 (s,1H)

EXAMPLE 35

2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoicacid hydroxyamide

2-(4-Methoxy-phenylsulfanyl)-pentanoic acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting fromethyl 2-bromovalerate (8.23 g, 39.3 mmol) and 4-methoxythiophenol (5 g,35.7 mmol), 10.46 g (100%); clear oil; MS: 269 (M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-pentanoic acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting from2-(4-methoxy-phenylsulfanyl)-pentanoic acid ethyl ester (6.9 g, 27.4mmol). Yield 7.07 g (86%); clear oil; MS: 300.9 (M+H)⁺.

Following the procedure as outlined in example 12,2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoicacid ethyl ester was prepared, starting from (3.0 g, 10.8 mmol) of2-(4-methoxy-benzenesulfonyl)-pentanoic acid ethyl ester and the4-[2-(chloromethyl-phenoxy)-ethyl]-morpholine (3.45 g, 11.9 mmol). Yield3.08 g, 62%; Brown oil; MS: 520.4 (M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholinlyl-ethoxy)-benzyl]-pentanoicacid ethyl ester (2.73 gm, 5.27 mmol) 1.45 g (Yield: 56%) of2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoicacid was isolated as colorless semi-solid by following the procedure asoutlined in example 9. MS: 492.3 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoicacid (1.01 g, 2.05 mmol) and following the procedure as outlined inexample 1, 190 mg of2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4yl-ethoxy)-benzyl]-pentanoicacid hydroxyamide was isolated as a brown solid. Yield 18%; mp 101° C.;MS: 507.4 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.71 (t, J=7 Hz, 3H),1.58-1.82 (m, 4 H), 3.12-3.98 (m, 12H), 3.87 (s, 3H), 4.35 (t, 2H) 6.89(d, J=8.7 Hz, 2H), 7.15 (m, 4H), 7.74 (d, J=8.9 Hz, 2H), 9.08 (s, 1H).

EXAMPLE 36

2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4Methoxy-benzenesulfonyl)-octanoicacid hydroxyamide

2-(4-Methoxy-phenylsulfanyl)-octanoic acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting fromethyl 2-bromooctanoate (11.8 g, 47.3 mmol) and 4-methoxythiophenol (6 g,43 mmol). Yield: 7.24 g (57%); clear oil; MS: 311.2 (M+H)⁺,2-(4-Methoxy-benzenesulfonyl)-octanoic acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting from2-(4-methoxy-phenylsulfanyl)octanoic acid ethyl ester (4.0 g, 13.6mmol). Yield 3.7 g (83%); clear oil; MS: 343.3 (M+H)⁺.

Following the procedure as outlined in example 12,2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-Methoxy-benzenesulfonyl)-octanoicacid ethyl ester was prepared, starting from (1.69 g, 5.18 mmol) of2-(4-methoxy-benzenesulfonyl)-octanoic acid ethyl ester and the1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane (1.73 g, 6.0 mmol). Yield4.86 g, 99%; Brown oil; MS: 574.5 (M+H)⁺.

Starting from2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-Methoxy-benzenesulfonyl)-octanoicacid ethyl ester (4.8 gm, 8.37 mmol) 1.55 g (Yield: 34%) of2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-Methoxy-benzenesulfonyl)-octanoicacid was isolated as colorless semi-solid by following the procedure asoutlined in example 9. MS: 551 (M+H)⁺.

Starting from2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-Methoxy-benzenesulfonyl)-octanoicacid (1.09 g, 2.0 mmol) and following the procedure as outlined inexample 1, 300 mg of2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-Methoxy-benzenesulfonyl)-octanoicacid hydroxyamide was isolated as a yellow solid. Yield 27%; mp 65° C.;MS: 561.6 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.81 (t, J=6.6 Hz, 3H),1.08-1.82 (m,14H), 3.13-3.51 (m, 12H), 3.87 (s, 3H), 4.33 (t, 2H) 6.88(d, J=8.7 Hz, 2H),7.14 (m,4H), 7.7 (d, J=9 Hz, 2H), 9.06 (s, 1H), 10.28(s, 1H).

EXAMPLE 37

2-(4-Methoxy-benzenesulfanyl)-octanoic acid hydroxyamide

2-(4-Methoxy-phenylsulfanyl)-octanoic acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting fromethyl 2-bromooctanoate (11.8 g, 47.3 mmol) and 4-methoxythiophenol (6 g,43 mmol). Yield: 7.24 g (57%); clear oil; MS: 311.2 (M+H)⁺.

Starting from 2-(4-Methoxy-benzenesulfanyl)-octanoic acid ethyl ester(3.1 gm, 10 mmol) 255 g (Yield: 90 %) of2-(4-Methoxy-benzenesulfanyl)-octanoic acid was isolated as colorlesssemi-solid by following the procedure as outlined in example 9. MS: 283(M+H)⁺.

Starting from 2-(4-Methoxy-benzenesulfanyl)-octanoic acid (4.25 g, 16mmol) and following the procedure as outlined in example 1, 3.64 g of2-(4-Methoxy-benzenesulfanyl)-octanoic acid hydroxyamide was isolated ascolorless solid. Yield: 76%, MP: 90 C; MS: 298.2 (M+H).

EXAMPLE 38

2-(4-Fluoro-phenylsulfanyl)-octanoic acid hydroxyamide

2-(4-Fluorophenylsulfanyl)-octanoic acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting fromethyl 2-bromooctanoate (6.47 g, 24.7 mmol) and 4-fluorothiophenol (3 g,23.4 mmol). Yield: 6.31 g (90%); clear oil; MS: 299 (M+H)⁺.

Starting from 2-(4-fluoro-benzenesulfanyl)-octanoic acid ethyl ester(3.1 gm, 10 mmol) 2.89 g (Yield: 100 %) of2-(4-fluoro-benzenesulfanyl)-octanoic acid was isolated as colorlesssemi-solid by following the procedure as outlined in example 9. MS:268.9 (M+H)⁺.

Starting from 2-(4-fluoro-benzenesulfanyl)-octanoic acid (2.49 g, 9.2mmol) and following the procedure as outlined in example 1, 2.72 g of2-(4-fluoro-benzenesulfanyl)-octanoic acid hydroxyamide was isolated ascolorless solid. Yield: 99%, MP: 58 C; MS: 284(M−H).

EXAMPLE 39

2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid hydroxyamide

2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid ethyl ester wasprepared according to the general method as outlined in example 9.Starung from ethyl 2-bromooctanoate (12.1 g, 48 mmol) and1-methyl-2-mercapto imidazole (5 g, 43.8 mnmol). Yield: 12 g (96%);clear oil; MS: 285 (M+)⁺.

Starting from 2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid ethylester (12 gm, 42.2 mmol) 10.2 g (Yield: 95%) of2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid was isolated ascolorless solid by following the procedure as outlined in example 9. MP:95 C, MS: 257.1 (M+H)⁺.

Starting from 2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid (7.84g, 30.6 mmol) and following the procedure as outlined in example 1, 2.77g of 2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid hydroxyamidewas isolated as colorless solid. Yield: 33%, MP: 125 C; MS: 272.2 (M+H).

EXAMPLE 40

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzensulfonyl)-3-naphthalen-2-yl-propionic acid ethylester was prepared, starting from (5.0 g, 20 mmol) of2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 2-bromomethylnaphthalene (4.4 g, 20 mmol). Yield 7.2 g, 91%; Colorless oil; MS: 399(M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionoicacid ethyl ester (3.7 g, 9 mmol) 3.3g (96%) of2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionoic acid wasisolated as colorless oil by following the procedure as outlined inExample 9. MS: 369.1 (M−H)⁻.

Starting from 2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionicacid (2.2 g, 5.9 mmol) and following the procedure as outlined inExample 1, 820 mg ofN-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionamidewas isolated as a light brown solid; Yield: 36%; mp 161-163° C.; MS:385.9 (+M)⁺; ¹H NMR (300 MHz, CDCl₃): δ 3.32 (d, 3-7.0 Hz, 1H), 3.69 (d,J=7.0 Hz, 1H), 3.82 (s, 3H), 5.02 (s, 1H), 6.92-7.89 (a, 11H).

EXAMPLE 41

N-Hydroxy-2-(4-methoxy-phenylmethanesulfonyl)-2-methyl-3-phenylpropionic acid hydroxamide

A mixture of 4methoxybenzyl mercaptan ( 7.0g, 45 mmol), ethyl2-bromopropionate (8.2 g, 46 mmol) and powdered oven dried potassiumcarbonate ( log, 72 mmol) in 150 mL of acetone was heated at reflux for18 h. The mixture was cooled, filtered, and the filtrate concentrated.The residue was taken up in 150 mL of methylene chloride, washed withwater (150 mL), dried over anhydrous sodium sulfate and evaporated toyield 12 g (99%); colorless liquid; MS 255.1 (M+H). This product is usedwithout further purification.

To an ice cold (5° C.) solution of2-(4-methoxy-phenylmethanesulfanyl)-propionic acid ethyl ester (5.7g, 21mmol) in 100 mL CH₂Cl₂ was added portionwise (7.2g, 40 mmol) ofm-chloroperbenzoic acid and the mixture was stirred for 1 h. Thereaction was diluted with hexanes (500 mL) and stirred at 25° C. for 30minute at room temperature. The mixture was filtered and the organiclayer treated with saturated aqueous sodium bisulfite (200 mL). Thehexanes solution containing the product was washed with water, dned(Na₂SO₄) and concentrated. Yield 5.5 g (91%); colorless oil; MS 287.1(M+H)⁺.

Following the procedure as outlined in Example 9,2-(4Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acidethyl ester was prepared, starting from2-(4-Methoxy-phenylmethanesulfonyl)-propionic acid ethyl ester (2 g, 7mmol) and benzyl bromide (1.3 g, 7.7 mmol). Yield 3.0 g, 100%; Lowmelting solid; MS: 377 (M+H)⁺.

2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid wasprepared starting from2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acidethyl ester (3.5 g, 9.0 mmol) dissolved in methanol (50 ml) and 10 NNaOH (30 ml). The resulting reaction mixture was worked up as outlinedin Example 9. Yield 930 mg, 31%. Colorless solid, mp: 106-108 C;. MS:347 (M−H)⁺.

Starting from2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid(2.7 g, 57.0 mmol) and following the procedure as outlined in example 1,266 mg ofN-Hydroxy-2-(4-methoxy-phenylmethanesulfonyl)-2-methyl-3-phenylpropionic acid hydroxamide was isolated as light colorless solid; Yield10%; mp 58-59° C.; MS: 364.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.28(s, 3H), 2.842.88 (d, 1H), 3.75 (s, 3H), 3.81-3.86 (d, 1H), 4.594.63 (d,1H), 4.694.74 (d, 1H), 6.94-6.98 (d, 2H), 7.19 (m, 2H), 7.29-7.33 (d,4H), 9.24 (s, 1H), 10.88 (s, 1H).

EXAMPLE 42

5-Methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hexenoic acidhydroxyamide

5-Methyl-2-(3-methyl-but-2enyl)-2-(toluenesulfonyl-hex-4-enoic acidethyl ester was prepared according to general method as outlined inexample 9. Starting from ethyl α-(p-tolylsulfonyl)acetate (2.9 g, 10.9mmol and 4bromo-2-methyl butene (3.42g, 23 mmol). Yield 4.6 g; tan oil;MS 379.2 (M+H)⁺.

5-methyl-2-(3-methyl-but-2-enyl)-2-(toluenefsulfonyl)-hexenoic acid wasprepared according to general method as outlined in example 9. Startingfrom 5-methyl-2-(3-methyl-but-2-enyl)-2-(toluenesulfonyl-hexfnoic acidethyl ester (4.5g, 11 mmol), ethanol (15 mL) and 10-N sodium hydroxide.

Starting fom5-methyl-2-(3-methyl-but-2-enyl)-2-(toluenefsulfonyl)-hexfnoic acid (4.1g, 11 mmol) and following the procedure as outlined in example 1, 1.07 gof 5-Methyl-2-(3-methyl-but-2-enyl)-2-(toluenefsulfonyl)-hex-4-enoicacid hydroxyamide was isolated as colorless solid; Yield: 30%; mp108-110° C.; MS: 366.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆: δ 61.49 (s,6H), 1.62 (s, 6H), 2.41 (s, 3H), 2.53-2.63 (m, 4H), 5.00-5.05 (t, 2H),7.40-7.43 (d, 2H), 7.59-7.62 (d, 2H), 9.04 (s, 1H), 10.80 (s, 1H).

EXAMPLE 43

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acidhydroxamide

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid ethylester (Prepared from 3-mercapto-2-methylfuran) was prepared according tothe general method as outlined in example 9. Starting from2-(2-methyl-furan-3-ylsulfanyl)-propionic acid ethyl ester (2.9g, 11.9mmol), benzyl bromide (2.22g, 13 mmol) and potassium carbonate (lOg) inacetone (75 mL). Yield (99%); amber oil; MS 337.1 (M+H)⁺.

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid wasprepared according to the general method as outlined in example 9.Starting from 2-(2-methyl-furan-3-ylsulfanyl)-propionic acid ethyl ester(4.8g, 14.3 mmol), dissolved in ethanol (25 niL and 10 N sodiumhydroxide (10 mL). Yield 3.7 g (84 %), white solid, MS 307.4 (M−H).

Starting from 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionicacid (3.58 g, 12 mmol) and following the procedure as outlined inexample 1, 1.078 g of2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acidhydroxyamide was isolated as orange color solid; Yield: 29%; mp 68-70°C.; MS: 324 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.27 (s, 3H), 2.81-2.86(d, 1H), 3.33 (s, 3H), 3.61-3.66 (d, 1H), 6.66 (s, IH), 7.19-7.25 (m,5H), 7.76 (s, 1H), 9.09 (s, 1H), 10.81 (s, 1H)

EXAMPLE 44

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-etoxy)-phenyl]-propionicacid hydroxamide

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4(2-piperidin-yl-ethoxy)-phenyl]-propionicacid ethyl ester was prepared according to the general method asoutlined in example 9. Starting from2-(2-methyl-furan-3-sulfonyl)-propionic acid ethyl ester (2.4g, 9.8mmol) and 1-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (2.96g, 10.7mmol); Yield 2.4 g (92%); amber oil; MS 464.2 (M+H)⁺.

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid was prepared according to the general method as outlined inexample 1. Starting from2-methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester (2.01 g, 4.5 mmol), dissolved in ethanol (20 mL) and 10N sodium hydroxide (10 mL). The resulting mixture was worked up asoutline in example 9. Yield 2.03g; amber crystals mp 66-68° C.; MS 434(M−H).

Starting from2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[(2-piperdin-1-yl-ethoxy)-phenyl]-propionicacid (2.03 g, 6.0 mmol) and following the procedure as outlined inexample 1, 1.36 g of2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[(2-piperdin-1-ylethoxy)-phenyl]-prpionicacid hydroxyamide was isolated as amber color solid; Yield: 32%; mp115-117 ° C; MS: 451.1 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.15-1.22(m, 2H), (1.75 (s, 3H), 1.78 (s, 3H) 2.98-3.03 (m, 2H), 3.42-3.47 (m,2H), 3.5 (s, 3H), 6.65 (s, 1H), 6.87-6.90 (d, 2H), 7.12-7.17 (d, 2H),10.35 (s, 1H), 10.60 (s, 1H), 11.70 (s, 1H).

EXAMPLE 45

2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propionicacid hydroxamide

2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl2-(thiophene-2-sulfonyl)-propionicacid ethyl ester was prepared acording to the general method as outlinedin example 9. Starting from 2-(thiophene-2-sulfonyl)-propionic acidethyl ester( prepared from 2-mercaptothiophene and 2-bromopropionic acidethylester) (4.4 g, 17.7 mnmol) and1-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (5.3 g, 19.5 mmol); Yield(96%); semi-solid; MS 466.

2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-]1-sulfonyl)-propionicacid was prepared acording to the general method as outlined in example9. Starting from2-methyl-3-([(2-piperidin-1-yl-ethoxy)-phenyl-2-sulfonyl)-propionic acidethyl ester (9.8g, 20 mmol), dissolved in ethanol (20 mL) and 10 Nsodium hydroxide (20 maL). The resulting mixture was worked up asoutline in example 1. Yield 4.5g (49%); white solid mp 170-172° C.; MS436.3 (M−H).

Starting from2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propionicacid (3.6 g, 8.0 mmol) and following the procedure as outlined inexample 1, 345 mg of2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propionicacid hydroxyamide was isolated as light colorless solid; Yield: 10%; mp115-118° C.; MS: 451.2 (M+H)⁺; ¹H NMR (300 MHz; DMSO-d₆): δ 31.29 (s,3H), 1.66-1.78 (m, 6H), 2.81-2.86 (d, 1H), 2.96-3.99 (m, 4H), 3.39-3.47(m, 2H), 3.51-3.59 (d, 1H), 4.32 (m, 2H),6.72-6.74 (d 1H), 6.87-6.96 (d,2H), 7.01-7.20 (m, 3H), 7.31-7.33 (m, 1H), 7.69-7.72 (m, 1H), 7.83-7.84(m, 1H), 8.07-8.08 (dd, 1H), 8.17 (dd, 1H), 9.0 (s, IH) 10.0 (s, 1H),10.78 (s, 1H).

EXAMPLE 46

2-(octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]propionic acidhydroxamide

2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyll-propionicacid ethyl ester was prepared according to the general method asoutlined in example 9. Starting from 2-(octane-1-sufonyl)-propionic acidethyl ester (5.0 g, 18 mmol) and1-[2-(4chloromethylphenoxy)-ethyl]-piperidine (5.6 g, 19.7 mmol); Yield8.9 g (96%); amber oil, MS 495.

2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionicacid was prepared according to the general method as outlined in example9. Starting from2-(octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl-3-propionicacid ethyl ester (8.9g, 18 mmol), ethanol (25 mL) and 10 N sodiumhydroxide (25 mL). Yield 6.0 g (72%).

Starting from2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionicacid (3.6 20 g, 7.7 mmol) and following the procedure as outlined inexample 1, 3.3 g of2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionicacid hydroxyamide was isolated as tan solid; Yield: 89%; mp 69-70° C.;MS: 483.2 (M+H)⁺; ¹H NMR (300 MHz, DMS O-d₆): δ 0.687 (t, 3H), 1.27-1.69(m, 15H), 2.71-2.75 (d, 1H), 3.51 (s, 3H), 3.65-3.69 (d, 1H), 6.86-6.89(d, 2H), 7.08-7.11 (d, 2H), 9.16 (s, 1H), 10.70 (s, 1H).

EXAMPLE 47

3-Biphenyl-4yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionicacid hydroxyamide

3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionicacid ethyl ester was prepared according to the general method asoutlined in example 9. Starting from2-methyl-(1-methyl-1H-imidazolesulfonyl)-propionic acid ethyl esterPrepared from (1-Methyl-2-mercapto imidazole and 2-bromo ethylpropionate) (3.0 g, 12.2 mmol) and 4 chloromethylbiphenyl (2.97 g,15mmol). Yield 5.0 g (99 %); low melting solid; MS 413 (M+H)⁺.

3-Biphenyl-4yl-2-methyl-2(1-methyl-1H-imidazole-2-sulfonyl)-propionicacid was prepared according to the general method as outlined in example9. Starting from3-biphenyl-4-yl-2-methyl2-(1-methyl-1H-imidazole-2-sulfonyl)-propionicacid ethyl ester (5.Og, 11.9 mmol), ethanol (15 mL) and 10 N sodiumhydroxide (10 mL). Yield 2.8g (61%); brown solid mp 119-122° C.; MS385.2 (M+H).

Starting from3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionicacid (2.8 g, 7.0 mmol) and following the procedure as outlined inexample 1, 112 mg of3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imiidazole-2-sulfonyl)-propionicacid hydroxyamide was isolated as tan colored solid; Yield: 4%; mp 112°C.; MS: 399.0 (M+H)⁺; ¹H NMR (300 Mz, DMSO-d₆): δ 0.911 (s, 3H), 3.3 (s,3H), 3.5 (d, 1H), 4.2 (d, 1H), 6.8 (d, 1H), 6.9 (d, 1H), 7.18-7.66 (m,5H), 7.30-7.33 (d, 2H), 7.55-7.58 (d, 2H).

EXAMPLE 48

2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid hydroxamide

2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid ethyl esterwas prepared according to the general method as outlined in example 9.Starting from 2-(thiophen-2-sulfonyl)-propionic acid ethyl ester (3.0 g,12 mmol) and benzyl bromide (2.48 g, 15 mmol). Yield 5.2 g (%); tan oil;MS 339.1 (M+H).

2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid was preparedaccording to the general method as outlined in example 9. Starting from2-methyl-3-phenyl-2-(thiophen-2-sulfonyl)-propionic acid ethyl ester(5.0 g, 15 mmol), ethanol (30 mL) and 10 N sodium hydroxide (10 mL).Yield 5.6g MS 310.0 (M+H).

Starting from 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid(5.0 g, 16 mmol) and following the procedure as outlined in example 1,1.8 g of 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acidhydroxyamide was isolated as colorless solid; Yield: 40%; mp 116-117°C.; MS: 325.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.29 (s, 3H), 3.33(d, 1H), 3.69 (d 1H), 7.18-7.30 (m, 5H), 7.74 (m, 1H), 8.22 (m, 1H),9.13 (s, 1H), 10.80 (s, 1H),

EXAMPLE 49

2-[8-(1-carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acidhydroxyamide

2-[8-(1-Carboxyl-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid ethylester was prepared according to the general method as outlined inexample 9. Starting from2-[4-(1-ethoxycarbonyl-ethylsulfanyl)octylsulfanyl]-propionic acid ethylester (10.2 g, 26 mmol) and sodium peroxymonopersulfate (64g, 104 mmol).Yield 9.87g (86%); colorless liquid; MS 442.9 (M+H).

2-[8-(1-Carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid wasprepared according to general method as outline in example 1. Startingfrom 2-[8-(1-carboxyethanesulfonyl)-octane-1 -suffonyl]-propionic acidethyl ester (3.0 g 6.8 mmol), ethanol (15 mL) and 10 N sodium hydroxide(15 nm). Yield 2.7 g (98%); wite solid mp 99-102 ° C.; MS 387 (M+NH3)⁺.

Starting from2-[8-(1-Carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid (2.5g, 6.5 mmol) and following the procedure as outlined in example 1, 641mg of 2-[8-(1-Carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acidhydroxyamidewas isolated as amber coloured oil.; Yield: 23%; MS: 434.0M+NH4)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.27-3.23 (m, 22H), 3.33 (m, 2H),8.9 (s, 1H), 9.28 (s, 1H).

EXAMPLE 50

2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionicacid hydroxamide

2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester was prepared according to general method as outlined inexample 9. Starting from ethyl α-(4-bromophenyl-sulfonyl) acetate (5.0g,16 mmol) and 1-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (4.97 g, 16mmol). Yield 6.1 g (71%); tan oil; MS 541.1 (M+H)⁺.

2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionicacid was prepared according to general method as outlined in example 9.Startingfrom2-(4-bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester (6.5 g, 20 mmol), ethanol (30 mL) and 10 N sodiumhydroxide (15 mL). Yield 6.3 g (100%); yellow solid mp 125-127° C.; MS512.5 (M+H)⁺.

Starting from2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperdine-1-yl-ethoxy)-phenyl]-propionicacid (6.1 g, 612 mmol) and following the procedure as outlined inexample 1, 1.07 g of2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionicacid hydroxyamide was isolated as light yellow solid; Yield: 17%; MS:525.4 (M+H)⁺.

EXAMPLE 51

3-(4-Bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide

Following the procedure as outlined in Example 9,3-(4-bromo-phenyl)-2-(4-methoxy-benzensulfonyl)-2-methyl-propionic acidethyl ester was prepared, starting from (3.0 g, 11 mmol)2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and4bromobenzyl bromide (3.0 g, 12 mmol). Yield 4.67 g, 96%; Colorless oil;MS: 441 (M+H)⁺.

3-(4-Bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acidwas prepared starting from3-(4-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acidethyl ester (4.0 g, 9.0 mmol) dissolved in methanol (50 ml) and 10 NNaOH (30 ml). The resulting reaction mixture was worked up as outlinedin Example 9. Yield 3.0 g, 78%. Low melting solid. MS: 413 (M+H)⁺.

Starting from3-(4-bromo-phenyl)-2-(4-methoxy-benzenesulfQnyl)-methyl-propionic acid(2.7 g, 6.5 mmol) and following the procedure as outlined in example 1,2.26 g of3-(4-bromophenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamidewas isolated as light colorless solid; Yield: 81%; mp 86-88° C.; MS:429.8 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 1.42 (s,3H), 1.77 (bs, 1H),3.26 (d, J=7.0 Hz, 1H), 3.68 (d, J=7.0 Hz, 1H), 3.85 (s, 3H), 7.01-7.76(m,8H), 9.71-9.88 (bs, 1H).

EXAMPLE 52

N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionic acidethyl ester was prepared, starting from (5.4 g, 20 mmol)2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and2-bromomethyl naphthalene (4.4 g, 20 mmol). Yield 8.0 g, 97%; Colorlesscrystals, mp 182-184° C.; MS: 413 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionic acidethyl ester (4.6 g, 11 mmol) 4.2g (98%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen 2-yl-propionic acidwas isolated as colorless crystals by following the procedure asoutlined in Example 9. mp144-146° C.; MS: 384.9 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionic acid(2.4 g, 6.2 mmol) and following the procedure as outlined in Example 1,1.6 g ofN-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionamidewas isolated as a light colorless solid; Yield: 64%; mp 185-187° C.; MS:400.2 (M+H)+; ¹H NMR (300 MHz, CDCl₃): δ 1.56 (s,3H), 3.28 (d, J=8.0 Hz,1H), 3.81 (d, J=8Hz, 1H), 3.93 (s,3H), 4.88 (bs, 1H), 7.02-7.92 (m,11H).

EXAMPLE 53

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-methyl-butyramide

2-(4-Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester wasprepared according to the general method as outlined in Example 1.Starting from ethyl 2-bromo-3-methyl-butanoate (20.9 g, 100 mmol) and4methoxybenzenethiol (14.0 g, 100 mmol), 30 g of2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester wasisolated. Yield 99%; Light yellow oil; MS: 269 (M+H)⁺.

Starting from 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethylester. (2.68 g 10 mmol) and following the procedure as outlined inExample 9 for oxidation, 3 g of2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid ethyl ester wasisolated as a colorless solid. yield: 99%; mp 53° C.; MS: 273 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid ethylester (3 g, 10 mmol) 2.7 g (96%) of2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid was isolated as acolorless solid by following the procedure as outlined in Example 9. Mp96° C.; MS: 273 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid (2.0g, 7.34 mmol) and following the procedure as outlined in Example 9, 590mg of N-hydroxy-2-(4methoxy-benzenesulfonyl)-3-methyl-butyramide wasisolated as a colorless solid. Mp 220° C.; Yield 28%; MS: 288 (M+H)⁺; ¹HNMR (300 Mz, DMSO₆): δ 0.88 (d, J=6.7 Hz, 3H), 1.07 (d, J=6.7 Hz, 3H),2.09-2.20 (bs, 1H), 3.53 (d, J=9, 1H), 7.12-7.17 (m, 2H), 7.74-7.79 (m,2H).

EXAMPLE 54

1-(4-Methoxy-benzenesulfonyl)cyclopentanecarboxylic acid hydroxyamide

Following the procedure as outlined in Example 9,1-(4methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid ethyl ester wasprepared, starting from (3.0 g, 11.6 mmol) of2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and1,Sdibromobutane (2.4 g, 7.6 mmol). Yield 2.4 g, 78%; Colorless solid,mp 86-88° C.; MS: 313 (M+H)⁺.

1-(4-Methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid was preparedstarting from 1-(4-methoxy-benzenesulfonyl)yclopentanecarboxylic acidethyl ester (2.2 g, 7.0 mmol) dissolved in methanol (50 ml) and 10 NNaOH (30 ml). The resulting reaction mixture was worked up as outlinedin Example 9. Yield 1.66 g, 83%. Colorless solid; mp 112-115° C.; MS:285 (M+H)⁺.

Starting from 1-(4-methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid(442 mg, 1.5 mmol) and following the procedure as outlined in Example 1,410 mg of 1-(4-methoxy-benzenesulfonyl)cyclopentanecarboxylic acidhydroxyamide was isolated as a colorless solid. mp 89-91° C.; Yield 88%;MS: 300 (M+H)⁺;¹H NMR (300 MHz, CDCl₃): δ 1.65-1.82 (m, 4H), 2.17-2.42(m, 4H), 3.87 (s, 3H), 7.0 (d, J=8Hz, 2H), 7.7 (bs, 1H), 7.72 (d, J=8Hz, 2H), 9.73 (bs, 1H).

EXAMPLE 55

3-(2-Bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide

Following the procedure as outlined in Example 9,3-(2-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acidethyl ester was prepared, starting from (2.0 g, 7.3 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and2-(bromo)benzyl bromide (2.0 g, 8 mmol). Yield 3.1 g, 87%; Colorlessoil; MS: 441 (M+H)⁺.

3-(2-Bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acidwas prepared starting from3-(2-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acidethyl ester (3.0 g, 68 mmol) dissolved in methanol (50 ml) and 10 N NaOH(30 ml). The resulting reaction mixture was worked up as outlined inExample 9. Yield 1.7 g, 63%. Waxy solid; MS: 414 (M+H)⁺.

Starting from3-(2-bromo-phenyl)2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid(470 mg, 1.1 mmol) and following the procedure as outlined in Example 9,380 mg of3-(2-bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamidewas isolated as a colorless solid. mp 93-96° C.; Yield 77%; MS: 429(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 1.3 (s, 3H), 3.32 (d, J=7.0 Hz, 1H),3.69 (d, J=7.0 Hz, 1H), 3.82 (s, 3H), 6.92-7.89 (m, 8H).

EXAMPLE 56

2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pentfenoic acidhydroxyamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-penttenoic acid ethylester was prepared, startipg from (3.0 g, 11 mmol) 2-(4methoxy-benzenesulfonyl)-propionic acid ethyl ester and cinnamyl bromide(2.1 g, 11 mmol). Yield 3.51 g, 82%; Colorless oil; MS: 389 (M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid wasprepared starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid ethylester (3.0 g, 11 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30ml). The resulting reaction mixture was worked up as outlined in Example9. Yield 1.9 g, 68%; yellowish oil; MS: 361 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid (440mg, 1.2 mmol) and following the procedure as outlined in Example 1, 420mg of 2-(4methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acidhydroxyamide was isolated as a colorless solid. mp 162-164° C.; Yield92%; MS: 376 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 1.41 (s, 3H), 3.0-3.16(m, 1H), 3.30 (d, J=1I Hz, 2H), 3.92 (s, 3H), 5.9 - 6.1 (m, 1H), 6.53(d, J=11 Hz, 1H), 7.1-7.72 (m, 9H), 9.12 (bs,1H).

EXAMPLE 57

2-(4-methoxy-benzenesulfonyl)5-phenyl-2-(3-phenyl-propyl)-pentanoic acidhydroxyamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoicacid ethyl ester was prepared, starting from (4.0 g, 15.8 mmol)2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 3-bromopropylbenzene (6.4 g, 32 mmol). Yield 3.7 g, 47%; Colorless oil; MS: 495(M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoicacid was prepared starting from2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoicacid ethyl ester (2.0 g, 4 mmol) dissolved in methanol (50 ml) and 10 NNaOH (30 ml). The resulting reaction mixture was worked up as outlinedin Example 9. Yield 1.18 g, 63%. Waxy solid; MS: 449.2 (M+H−H₂O)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoicacid (600 mg, 1.2 mmol) and following the procedure as outlined inExample 1, 420 m; of2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoicacid hydroxyamide was isolated as a colorless solid. Mp 118-120° C.;yield 68%; MS: 482 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 1.52-1.68 (m, 2H),1.74-1.92 (m, 2H), 1.98-2.20 (m, 4H), 2.58 - 2.72 (m,4H), 3.86 (s, 3H),6.93 (d, J=11 Hz, 2H), 7.02-7.63 (m, 10OH), 7.81 (d, J=11 Hz, 2H).

EXAMPLE 58

2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyamide

Following the procedure as outlined in Example 9,2-allyl-2-(4methoxy-benzenesulfonyl)-pent-4-enoic acid ethyl ester wasprepared, starting from (3.0 g, 11.6 mmol)2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and allyl bromide(4 ml, excess). Yield 3.6 g, 92%; Yellow oil; MS: 338 (M+H)⁺.

2-Allyl-2-(4-methoxy-benzenesulfonyl)-pentenoic acid was preparedstarting from 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acidethyl ester (2.2 g, 6.5 mmol) dissolved in methanol (50 ml) and 10 NNaOH (30 ml). The resulting reaction mixture was worked up as outlinedin Example 9. Yield 1.76 g, 87%; yellowish oil; MS: 311 (M+H)⁺.

Starting from 2-allyl-2-(4-methoxy-benzenesulfonyl)-pentAenoic acid (1.5g, 4.8 mmol) and following the procedure as outlined in Example 1, 1.5 gof 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyamidewas isolated as colorless solid Mp 114-116° C.; Yield 99%; MS: 326(M+H)⁺; ¹H NMR (300 MD, CDCl₃): δ 1.62 (s, 1H), 2.70-2.80 (m,4H), 3.9(s, 3H), 5.16-5.27 (m, 4H), 5.81-5.94 (m, 2H), 7.12 (d,J=8 Hz,2H).

EXAMPLE 59

2-(4-methoxy-benzenesulfonyl)-2-propyl-pentanoic acid hydroxyamide

2-allyl-2-(4-methoxy-benzenesuifony1)-pentenoic acid hydroxyamide (326mg, 1.0 mmol) (example 26) was dissolved in methanol (50 ml) andhydrogenated over 10% Pd/C (100 mg) at room temperature, under 49 psipressure for 4 hours. At the end, the reaction mixture was filtered andmethanol was removed. The resulting solid was crystallized frommethanol. Yield: 250 mg, 75%; MS: 330 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ0.92 (t, J=4.0 Hz, 6H), 1.27-1.59 (m, 4H), 1.78-2.02 (m, 4H), 3.86 (s,3H), 6.04 (bs, 1H), 6.97 (d, J=9Hz, 2H), 7.76 (d, J=9 Hz, 2H).

EXAMPLE 60

2-benzyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide

Following the procedure as outlined in Example 9,2-benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethylester was prepared, starting from (1.0 g, 3.8 mmol) of2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and benzylbromide(4 ml, excess). Yield 1.2 g, 72%; Yellow oil; MS: 439 (M+H)⁺.

2-Benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid wasprepared starting from2-benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethylester (1.0 g, 2.2 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30ml). The resulting reaction mixture was worked up as outlined in Example9. Yield: 580 mg, 62%; Waxy solid; MS: 409 (M−H)⁻.

Starting from 2-benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyI-propionicacid (410 mg, 1 mmol) and following the procedure as outlined in Example1, 225 mg of2-benzyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamidewas isolated as a waxy solid Yield 52%; MS: 426 (M+H)⁺; ¹H NMR (300 MD,CDCl₃): δ 3.25 (d, J=14 Hz, 2H), 3.52 (d, J=14 Hz, 2H), 3.9 (s, 3H),6.93 (d, J=8Hz, 2H), 7.02-7.26 (m, 9H), 7.61 (d, J=8 Hz, 2H), 7.87 (d,J=4Hz, 1H), 9.58 (bs, IH).

EXAMPLE 61

N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionamide

To a stirred solution of 2-(4-methoxy-benzenesulfonyl)propionic acidethyl ester (2.7 gm, 10 nmmol), 3-picolyl chloride hydrochloride (3.2 g,20 mmol). and triethyl benzylammonium chloride (1 g) in methylenechloride (400 ml), 10 N NaOH (30 ml) was added. The reaction wascontinued at room temp for 48 hours. At the end, the organic layer wasseparated and washed well with water. The organic layer was dried,filtered and concentrated. The crude product obtained was purified bysilica-gel column chromatography. The column was eluted with 50% ethylacetate: hexane.2-(4-Methoxy-benzensulfonyl)-2-methyl-3-pyridin-3-yl-propionic acidethyl ester was isolated as brown oil. Yield 3.0 g, 82%; Brown oil; MS:364 (M+H).

Starting, from2-(4-methoxy-benzenesulfonyl)-2-methyl3pyrdin-3-yl-propionic acid ethylester (2.5 g, 6.8 mmol) 1.8 g (79%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid wasisolated as a colorless solid by following She procedure as outlined inExample 9. mp 58° C.; MS: 336 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid(410 mg, 1 mmol) and following the procedure as outlined in Example1,225 mg ofN-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionamidewas isolated as a colorless solid. Yield 52%; mp 98° C.; MS: 351 (M+H)⁺;¹H NMR (300 MHz, CDCl₃): δ 1.4 (s, 3H), 3.1 (d, J=9.0, 1H), 3.65 (d,J=9.1, 1H), 3.9 (s, 3H), 7-8.5 (m, 8H).

EXAMPLE 62

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethy1ecanoic acidhydroxyamide

Starting from 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (7.5g, 29 mmol) and 1-bromooctane (6.7 g, 35 mmol) 8 g of the mono octylatedcompound 2-(4-methoxy-benzenesulfonyl)-decanoic acid ethyl ester wasisolated by following the procedure outlined in Example 9. Yield: 8.0 g74%; MS: 370 (M+H)⁺.

Following the procedure as outlined in example 29,2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid ethylester was prepared, starting from (8.0 g, 21.6 mmol) of2-(4-methoxy-benzenesulfonyl)-decanoic acid ethyl ester and 3-picolylchloride hydrochloride (4.1 g, 25 mmol). Yield 6.5 g, 68%; Brown oil;MS: 462 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid ethylester (5.0 g, 11 mmol), 4.5g (91%) of2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid wasisolated as a colorless solid by following the procedure as outlined inExample 9. Mp 159° C.; MS: 434 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid (2.5 g,5.7 mmol) and following the procedure as outlined in Example 1, 1.4 g of2-(4methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyldecanoic acidhydroxyamide was isolated as colorless solid. Yield: 50%; mp 62° C.; MS:448 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 0.86 (t, 6.9 Hz, 3H), 1.25-2.17(m, 14 H), 3.3 (d, J=14 Hz, 1H), 3.5 (d, J=14 Hz, 1H), 3.9 (s, 3H),6.8-8.6 (m, 8H).

EXAMPLE 63

2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoicacid hydroxyamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-5-methyl-hexenoic acid ethyl ester wasprepared, starting from (6.0 g, 23 mmol)2-(4methoxy-benzenesulfonyl)-acetic acid ethyl ester and isoprenylbromide (3.0 ga 20 mmol). Yield 6.52 g, 86%; Colorless oil; MS: 327(M+H)⁺.

Following the procedure as outlined in Example 29,2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoicacid ethyl ester was prepared, starting from (4.0 g, 12.2 mmol) of2-(4-methoxy-benzenesulfonyl)-5-methyl-hex-4-enoic acid ethyl ester and3-picolylchloride hydrochloride (2.1 g, 13 mmol). Yield 4.14 g, 81%;Brown oil; MS: 418 (M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoicacid was prepared starting from2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexenoicacid ethyl ester (4.0 g, 9.5 mmol) dissolved in methanol (50 ml) and 10N NaOH (30 ml). The resulting reaction mixture was worked up as outlinedin Example 9. Yield 3.2 g, 87%; ivory solid; mp 117-119° C.; MS: 390(M+)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoicacid (2.1 g, 5.4 mmol) and following the procedure as outlined inExample 1, 1.82 g of2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoicacid hydroxyamide was isolated as a colorless solid. Yield: 82%; mp89-92° C.; MS: 405 (M+H)⁺; ¹H NM (300 MHz, CDCl₃): δ 1.63 (s, 3H), 1.76(s, 3H), 2.62-2.78 (m, 2H), 3.3 (d, J=4.0 Hz, 1H), 3.63 (d, J=4.0 Hz,1H), 3.82 (s, 3H), 5.26 (m, lH), 7.12-7.88 (m, 6H), 8.27-8.33 (m, 2H).

EXAMPLE 64

2-Benzyl-4-diisopropylamino-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-butyramide

Following the procedure as outlined in Example 29,2-benzyl4-diiiopropylamino-2-(4 methoxy-benzenesulfonyl)-butyric acidethyl ester was prepared, starting from (3.0 g, 8.5 mmol) of2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester(Example 9) and 2-diisopropylaminoethyl chloride hydrochloride (4.0 g,20 mmol). Yield 3.2 g, 79%; Ivory solid, mp 89-91° C.; MS: 476.4 (M+H)⁺.

Starting from2-benzyl-4-disopropylaniino-2-(4-methoxy-benzenesulfonyl)-butync acidethyl ester (3.53 gm, 7.5 mmol) 2.8 g (86%) of2-benzylA-diisopropylamino-2-(4-methoxy-benzenesulfonyl)-butyric acidwas isolated as colorless crystals by following the procedure asoutlined in Example 9. Mp 136-138° C.; MS: 448.5 (M+H)⁺.

Starting from2-benzyl-4-diisopropylamino-2-(4-methoxy-benzenesulfonyl)-butyric acid(1.85 g, 4.1 mmol) and following the procedure as outlined in Example 1,1.3 g of2-benzyl-4-diisopropylamino-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-butyramidewas isolated as a low melting waxy solid; Yield: 68%; MS: 463.3 (M+H)⁺;¹H NMR (300 MHz, CDCl₃): δ 0.98 (d, J=11 Hz, 6H), 1.16 (d, J=11 Hz, 6H),1.92 (m, 2H), 2.46 (m, 2H), 2.71 (m, 2H), 3.18 (m, 1H), 3.48 (m, 1H),3.86 (s, 3H), 6.98 (d, J=8 Hz, 2H), 7.18-7.22 (m, 5H), 7.92 (d, J=8 Hz,2H), 8.12 (s, 1H).

EXAMPLE 65

3-Cyclohexyl-N-hydroxy-2-(4-methoxy-bcnzenesulfonyl)-2-pyridin-3-ylmethyl-propionamide

Following the procedure as outlined in Example 9,3-cyclohexyl-2-(4methoxy-benzenesulfonyl)-propionic acid ethyl ester wasprepared, starting from (4.0 g, 15 mmol)2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 1-bromomethylcyclohexane (2.7 g, 15 mmol). Yield 5.0 g, 94%; Colorless oil; MS: 355(M+H)⁺.

Following the procedure as outlined in Example 29,3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionicacid ethyl ester was prepared, starting from3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-propionic acid ethylester(1.5 g, 4.2 mmol) and 3-picolyl chloride (1.0 g, 6 mmol). Yield 1.0g, 38%; Colorless oil; MS 446 (M+H)⁺.

Starting from3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionicacid ethyl ester (1.3 g, 2.9 mmol) 1.0 g (83%) of3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionicacid was isolated as colorless crystals by following the procedure asoutlined in Example 9. Mp 92° C. MS: 417.5 (M+H)⁺

Starting from3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionicacid (1.0 g, 2.4 mmol) and following the procedure as outlined inExample 1, 80 mg of3-cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyI)-2-pyndin-3-ylmethyl-propionamidewas isolated as a colorless hydrochloride salt; Yield: 71%; mp 57-60 °C; MS: 433 (M+H)+; ¹H NMR (300 MHz, CDCl₃): δ 0.8-2.08 (m, 13 H), 3.3(d, J=14 Hz, 1H), 3.7 (d, J=14 Hz, 1H), 3.9 (s, 3H), 7.0-8.5 (m, 8H).

EXAMPLE 66

2-(4-Methoxy-benzenesulfonyl)-4-methyl-2-pyrdin-3-yh nethyl-pentoic acidhydroxyamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-4-methyl-pentanoic acid ethyl ester wasprepared, starting from (5.0 g, 20 mmol)2-(4methoxy-benzenesulfonyl)-acetic acid ethyl ester and1-bromo-2-methyl propane (2.6 g, 20 mmol). Yield 6.0 g, 95%; Colorlessoil; MS: 315 (M+H)⁺.

Following the procedure as outlined in Example 29,2-(4-methoxy-benzenesulfonyl) methyl-2-pyridin-3-ylmethyl-penanoic acidethyl ester was prepared, starting from (3.1 g, 10 mmol) of2-[(4-methoxy-benzenesulfonyl)-4-methyl pentanoic acid ethyl ester and3-picolyl chloride hydrochloride (1.8 g, 11 mmol). Yield 3.0 g, 75%;Colorless oil; MS: 406 (M+H)⁺.

Starting from2-4-methoxy-benzenesulfonyl)-4-methyl-2-pyrdin-3-ylmethyl-pentanoic acidethyl ester (1.2 g, 2.9 mmol) 1.0 g (91%) of2-(4-methoxy-benzenesulfonyl)4-methyl-2-pyridin-3-ylmethyl-pentanoicacid was isolated as colorless crystals by following the procedure asoutlined in Example 9. Mp 188-186° C.; MS: 378 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-4medyl-2-pyrdin-3-ylmethyl-pentanoic acid(800 mg, 2.1 mmol) and following the procedure as outlined in Example 1,180 mg of2-(4-methoxy-benzenesulfonyl)-4-methyl-2-pyridin-3-ylmethyl-pentanoicacid hydroxyamide was isolated as a colorless solid; Yield: 21%; mp 78°C.; MS: 393.4 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 0.65 (d, 6.3 Hz, 3H),0.89 (d, J=6.2 Hz, 3H), 1.7 (m, IH), 2.06 (m, 2H), 3.85 (s, 3H), 6.8-8.5(m, 10H).

EXAMPLE 67

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionamide

Following the procedure as outlined in Example 29,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionic acidethyl ester was prepared, starting from (5.2 g, 20 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and7-bromomethyl quinoline (4.4 g, 20 mmol). Yield 4.5 g, 54%; Pale yellowsolid; mp 86 ° C; MS: 414 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6yl-propiolic acidethyl ester ( 3.0 gm, 7.2 mmol) 2.5g (90%) of2-(4methoxy-benzenesulfonyl)-2-methyl-3uinolin 6-yl-propionic acid wasisolated as colorless crystals by following the procedure as outlined inExample 9. mp 106-108° C.; MS: 386.4 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionic acid(2.0 gm, 5.2 mmol) and following the procedure as outlined in Example 1,1.2 g ofN-hydroxy-2-(methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionamidewas isolated as a colorless solid; Yield: 57%; mp 206° C.; MS: 401.4(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 1.4 (s, 3H), 3.19 (m, 1H), 3.8 4.0(m, 4H), 7.1-8.95 (m, 12H).

EXAMPLE 68

2-(4-Methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-yhnethyl-hexanoicacid hydroxyamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-6-phenoxy-hexanoic acid ethyl ester wasprepared, starting from (2.5 g, 10 mmol)2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 1-bromophenoxybutane (2.2, 10 ramol). Yield 3.8 g, 93%; Colorless oil; MS: 407 (M+H)⁺.

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoicacid ethyl ester was prepared, starting from (3.1 g, 10 mmol)2-(4-methoxy-benzenesulfonyl)-6-phenoxy-hexanoic acid ethyl ester and3-picolyl chloride (1.8 g, 11 mmol). Yield 3.5 g, 71%; Colorless oil;MS: 498 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoicacid ethyl ester (3.0 g, 6.0 mmol), 2.8 g (Yield: Quantitative) of2-(4methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoicacid was isolated as colorless crystals by following the procedure asoutlined in Example 9. Mp 148-151° C.; MS: 470.5 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoicacid (2.0 g, 4.3 mmol) and following the procedure as outlined inExample 1, 1.5 g of2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoicacid hydroxyamide was isolated as a colorless solid; Yield: 72%; mp 68°C.; MS: 485.5 (M+H)+; ¹H NMR (300 MHz, CDCl₃): δ 1.5-2.5 (m, 8H), 3.4(bs, 2H), 3.8 (s, 3H), 6.8-8.7 (m, 13H).

EXAMPLE 69

2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoicacid hydroxyamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-5-hexanoic acid ethyl ester was prepared,starting from (10.0 g, 39 mmol) 2-(4methoxy-benzenesulfonyl)-acetic acidethyl ester and 1-bromo-3-methyl butane ( 6.0 g, 40 mmol). Yield 8.5 g,62%; Colorless oil; MS: 329 (M+H)⁺.

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoicacid ethyl ester was prepared, starting from (6.0 g, 18 mmol) of2-(4-methoxy-benzenesulfonyl)-5-methyl-hexanoic acid ethyl ester andpicolyl chloride hydrochloride (4.1 g, 25 mmol). Yield 4.5 g, 60%; Brownoil; MS: 420 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoicacid ethyl ester (3.0 g, 7.1 mmol) 2.6 g (92%) of2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoicacid was isolated as a colorless solid by following the procedure asoutlined in Example 9. Mp: 173 C; MS: 392 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridi-3-ylmethyl-hexanoic acid(1.0 g, 2.5 mmol) and following the procedure as outlined inExample 1,800 mg of2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoicacid hydroxyamide was isolated as a colorless solid; The hydrochloridewas prepared byr passing hydrogen chloride gas through methanol solutionof the hydroxyarnide. Yield: 72%; mp 62 ° C (HCl salt); MS: 408 (M+H)⁺;¹H NMR (300 MHz, CDCl₃): δ 0.76 (m, 611), 1.2 -2.0 (5H), 3.5 (bq, 2H),7.1-8.8 (m, 8H), 11.1 (bs,1H).

EXAMPLE 70

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acidhydroxyamide

(4-Methoxy-phenylsulfanyl)-acetic acid tert-butyl ester was preparedaccording to the general method as outlined in Example 1. Starting fromthe corresponding 1-bromo tert-butyl acetate (5.3 g, 27 mmol) and4-methoxybenzenethiol (3.7 g, 27 im=ol), 6.4 g of the product wasisolated. Yield 98%; Light yellow oil; MS: 255 (M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-acetic acid tert-butyl ester was preparedaccording to the general method as outlined in Example 9. Staring from2-(4-methoxy-benzenesulfanyl)-acetic acid tert-butyl ester (5.0 g, 20mmol) and 3-chloroperoxybenzoic acid 57% (12.0g, 40 mmol), 5.3 g of theproduct was isolated. Yield 92%; Waxy solid; MS: 287.1 (M+H)+.

2-(4-Methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butylester was prepared according to the procedure as outlined in Example 9.Starting from 2-(4-methoxy-benzenesulfonyl)acetic acid tert-butyl ester(20.0 g, 70.0 mmol) and 3-picolyl chloride (7.28 g, 44.4 mmol), 10.5 gof the product was isolated by silica gel chromatography (50% ethylacetate: hexane). Yield 63%; white solid; mp 93-94° C.; MS: 378.0(M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acidtert-butyl ester was prepared according to the procedure as outlined inExample 9. Starting from2-(4-methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butylester (2.0 g, 5.3 mmol) and n-butyl bromide (0.73 g, 5.3 mmol), 1.20 gof the product isolated. Yield 52%; yellowish gum; MS: 434.3 (M+H)⁺.

A mixture of the2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acidtert-butyl ester (1.1 g, 2.5 mmol), in methylene chloride/TFA (1:1) wasstirred at room temperature for about 2 hours. The solvents were thenevaporated and the2-T4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid waspurified by silica gel chromatography (30% methanol/methylene chloride).Yield 0.90 g, 94%; white solid; mp 10 ° C; MS: 376.1 (M−H)⁻.

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acidhydfoxyamide was prepared according to the method as outlined inExample 1. Starting from2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid (0.31g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.13 gof the product isolated. Yield 37%; pale yellowish solid; mp 65° C.; MS:392.9 (MN+H)⁺; ¹H NMR (300 MHz, DMSO-d6) 5 0.80 (t, J=7.2 Hz, 3H),1.10-1.25 (m, 2H), 1.25-1.50 (m, 2H), 1.70-2.00 (m, 2H), 3.53 (d, J=14.4 Hz, 1H), 3.62 (d, J=14.4 Hz, 1H), 3.88 (s, 3H), 7.15 (d, J =8.9Hz, 2H), 7.71 (d, J =8.9 Hz, 2H), 7.90-8.00 (m, 1H), 8.40-8.45 (m, 1H),8.70-8.85 (m, 2H), 11.0 (brs, 1H); IR (KBr, cm-l): 3064m, 2958s, 2871m,1671m.

EXAMPLE 71

2-(4-methoxy-benzenesulfonyl)-2-oct-2-ynyl-decffynoic acid hydroxyamide.

The title compound was prepared according to the procedure as outlinedin example 9. Starting from 2-(4-methoxy-benzenesulfonyl)-acetic acidtert-butyl ester (2.86 g, 10 mmol) and 1-bromo-2-octyne (3.80 g, 20mmol), 4.4 g of the product isolated. Yield 100%; yellowish gum; MS:446.9 (M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec4-ynoic acid was preparedaccording to the method as outlined in example 70. Starting from2-(4-methoxy-benzenesulfonyl)-2-oct-2-ynyl-decynoic acid tert-butylester (4.40 g, 10.0 mmol), 2.0 g of the product isolated. Yield 49%;white solid; mp 61° C.; MS: 345.1 (M−H)⁻.

2-(4-Methoxy-benzenesulfonyl)-2-oct-2-ynyl-decwynoic acid hydroxyamidewas prepared according to the method as outlined in example 1. Startingfrom 2-(4-methoxy-benzenesulfonyl)-2-oct-2-ynyl-decfynoic acid (0.36 g,0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.25 g ofthe product isolated. Yield 62%; white solid; mp 83-84° C.; 462.0(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 0.82-0.90 (m, 6H), 1.15-1.45 (m,12H), 1.90-2.05 (m, 4H), 2.86 (brd, J =17.0 Hz, 2H), 3.00 (brd, J=17.0Hz, 2H), 3.87 (s, 3H), 7.15 (d, J=10.0 Hz, 1H), 7.71 (d, J3=10.0 Hz,IH), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm⁻¹): 3344s, 3208m,2930m, 2870m, 1677s, 1592s; Anal. Calc'd for C₂₅H₃₅NO₅S: C, 65.05; H,7.64; N, 3.03. Found: C, 65.26; H, 7.68; N, 2.90.

EXAMPLE 72

2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hextynoic acid hydroxyamide

2-(4Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex4-ynoic acid tert-butylester was prepared according to the procedure as outlined in Example 9.Starting from 2-(4methoxy-benzenesulfonyl)-acetic acid tert-butyl ester(2.86 g, 10 mmol) and 1-bromo-2-butyne (2.68 g, 20 mmol), 3.50 g of theproduct was isolated. Yield 90%; white solid; mp 85-87° C.; MS: 391.0(M+H)⁺.

2-(4Methoxy-benzenesulfonyl)-2-but-2-ynyl-hextynoic acid was preparedaccording to the procedure as outlined in example 70. Starting from2-(4-methoxy-benzenesulfonyl)-2-but-2-ynyl-hextynoic acid tert-butylester (3.0 g, 7.7 mmol), 2.5 g of the product isolated. Yield 97%; whitesolid; mp 141-143° C.; MS: 333.1 (M−H)⁻.

2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hexynoic acid hydroxyamidewas prepared according to the method as outlined in example 1. Staringfrom 2-(4-methoxy-benzenesulfonyl)-2-but-2-ynyl-hexfynoic acid (0.27 g,0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.23 g ofthe product was isolated. Yield 89%; white solid; mp 135-137° C.; MS:349.9 (M+H)⁺1; ¹H NMR (300 MHz, DMSO-d6) 5 1.67 (s, 6H), 2.70-3.10 (m,4H), 3.88 (s, 3H), 7.15 (d, J=10.0 Hz, 2H), 7.71 (d, J =10.0 Hz, 2H),9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm-1): 3301s, 3161m, 2922m,1640m, 1595s, 1500m.

EXAMPLE 73

2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pentynoic acid hydroxyamde

2-(4Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent4ynoic acid tert-butylester was prepared according to the procedure as outlined in Example 9.Starting from 2-(4methoxy7, benzenesulfonyl)-acetic acid tert-butylester (2.0 g, 7.0 mmol) and propargyl bromide (1.77 g, 15 mmol), 1.90 gof the product was isolated. Yield 75%; white solid; mp 113-1 15° C; MS:362.1 (M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent4ynoic acid was preparedaccording to the procedure as outlined in Example 70. Starting, from2-(4methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent4-ynoic acid tert-butylester (1.70 g, 4.7 mmol), 1.30ga of the product isolated. Yield 90%;white solid; mp 156° C.; MS: 305.1 (M−H)⁻.

2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent4ynoic acid hydroxyamidewas prepared according to the method as outlined in Example 1. Startingfrom (4methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid (0.25 g,0.81 minol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.22 g ofthe product was isolated. Yield 85%; white solid; mp 156° C.; MS: 321.9(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.00-2.13 (m, 2H), 3.00-3.30 (m,4H), 3.90(s, 3H), 7.01 (d, J=9.0 Hz, 2H), 7.82 (d, J =9.0 Hz, 2H), 8.76(brs, 1H), 10.65 (brs, 1H); IR (KBr, cm-1): 3392s, 3293s, 3271m, 2955m,1650s, 1594s; Anal. Calc'd for C₁₅H₁₅NO₅S: C, 56.07; H, 4.70; N, 4.36.

Found: C, 55.65; H, 4.67; N, 4.10.

EXAMPLE 74

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decfynoic acidhydroxyamide

The title compound was prepared according to the procedure as outlinedin Example 38. Starting from2-(4-methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butylester (2.20 g, 5.8 mmol) and 1-bromo-2-octyne (1.14 g, 6 mmol), 2.60 gmof the product isolated. Yield 92%; yellowish gum; MS: 486.0 (M+H)⁺.

A mixture of the2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decfynoic acidtert-butyl ester (2.60 g, 5.35 mmol), in methylene chloridenTFA (1: 1)is stirred at room temperature for about 2 hours. (Ref. example 70) Thesolvents are then evaporated and the2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyldecynoic acid waspurified by silica gel chromatography (˜30% methanoL/methylenechloride). Yield: 2.0 g, 87%; White solid; mp 146° C.; MS: 428.1 (M−H)⁻.

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec4-yrioic acidhydroxyamide was prepared according to the procedure outlined inExample 1. Starting from2-(4methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decfynoic acid (0.71g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.48 gof the product was isolated. Yield 67%; off-white solid; mp 65° C.; MS:445.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=6.8 Hz, 3H),1.10-1.40 (m, 6H), 1.85-2.00 (m, 2H), 2.79 (d, J 17.9 Hz, 1H), 2.90 (d,J=17.9 Hz, 1H), 3.50 (d, J=13.7 Hz, 1H), 3.74 (d, J =13.7 Hz, 1H), 3.89(s, 3H), 7.19 (d, J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.85-7.89 (m,1H), 8.37-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.0 (brs, 1H); IR (KBr,cm-1): 3157m, 3095m, 2954s, 2932s, 2858m, 1671m, 1593s;

Anal. Calc'd for C₂₃H₂₈N₂O₅S.HCl.0.9H₂O: C, 55.56; H, 6.24; N, 5.63.

Found: C, 55.84; H, 6.19; N, 5.59.

EXAMPLE 75

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent4fynoic acidhydroxyamide

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-penttynoic acidtert-butyl ester was prepared according to the procedure as outlined inExample 38. Starting from2-(4-methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butylester (3.77 g, 10 mmol) and propargyl bromide (1.74 g, 13 mmol), 2.50 gof the product was isolated. Yield 60%; yellowish solid; mp 132-133° C.;MS: 416.0 (M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pentAynoic acid wasprepared according to the procedure as outlined in Example 70. Startingfrom 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoicacid tert-butyl ester (2. 0 g, 4.8 mmol), 1.2 g of the product isolated.Yield 69%; white solid; mp 119-121° C; MS: 358.1 (M−H)⁻.

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent4-ynoic acidhydroxyamide was prepared according to the method as outlined inExample 1. Starting from2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pentfynoic acid (0.29g, 0.81 mmol) and hydroxylarnine hydrochloride (0.70 m, 10 mmol), 0.065g of the product was isolated. Yield 25%; off-white solid; mp 70° C.;MS: 375.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.19 (brs, 1H), 2.90-3.00(m, 2H), 3.55 (d, J=13.8 Hz, 1H), 3.67 (d, J =13.8 Hz, 1H), 3.89 (s,3H), 7.18 (d, J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H, 7.80-7.89 (m, 1H),8.35-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (brs, 1H); IR (KBr, cm-l):3168m, 3095s, 1670m, 1593s.

EXAMPLE 76

2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex4-ynoic acidhydroxyamide

2-(4-Fluoro-benzenesulfanyl)-acetic acid tert-butyl ester was preparedaccording to the procedure as outlined in Example 1. Starting from4-fluorothiophenol (30.0 g, 230 mmol) and tert-butyl bromoacetate (45.67g, 230 mmol), 53.4 g of the product was isolated. Yield 100%; paleyellowish oil; MS: 243.1 (M+H)⁺.

2-(4-Fluoro-benzenesulfonyl)-acetic acid tert-butyl ester was preparedaccording to the general method as outlined in Example 9. Starting from2-(4-fluoro-benzenesulfanyl)-acetic acid tert-butyl ester (48.4 g, 200mmol) and 3-chloroperoxybenzoic acid (121.3g (57%), 400 mnmol), 48.0 gof the product was isolated. Yield 88%; pale yellowish oil; MS: 275.1(M+H)⁺.

The title compound was prepared according to the procedure as outlinedin Example 70. Starting from2-(4-fluoro-benzenesulfonyl)-3-pyridin-3-ylpropionic acid tert-butylester (1.83 g, 5.0 mmol) and 1-bromo-2-butyne (0.67 g, 5.0 mmol), 2.18 gof the product was isolated Yield 100%; yellowish gum; MS: 419.2 (M+H)⁺.

2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex4ynoic acid wasprepared according to the method as outlined in Example 38. Startingfrom 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acidtert-butyl ester (2.1 g, 5.0 mmol), 1.20 g of the product was isolated.Yield 67%; off-white solid; mp 150° C.; MS: 360.2 (M−H)⁻.

2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl- hexynoic acidhydroxyamide was prepared according to the method as outlined inExample 1. Starting from2-(4fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hextynoic acid (0.29 g,0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.15 g ofthe product was isolated. Yield 45%; white solid; mp 190° C.; MS: 377.2(M+H)⁺; ¹H NIR (300 MHz, DMSO-d₆) δ 1.60 (s, 3H), 2.70-3.00 (m, 2H),3.53 (d, J=13.8 Hz, IH), 3.74 (d, J3=13.8 Hz, 1H), 7.50-7.58 (m, 2H),7.80-7.95 (m, 3H), 8.35-8.40(m, 1H), 8.748.79 (m, 2H), 11.1 (brs, 1H);IR (KBr, cm-1): 3154m, 3105s, 3068s, 2875m, 1696s, 1630w, 1590s;

Anal. Calc'd for C₁₈H₁₇FN₂O₄.SHCl,0.5H₂O: C, 51.24; H, 4.54; N, 6.64.

Found: C, 51.21; H, 4.35; N, 6.46.

EXAMPLE 77

2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-decfynoic acidhydroxyamide

The title compound was prepared according to the procedure as outlinedin Example 9. Starting from2-(4-fluoro-benzenesulfonyl)-3-pyridin-3-ylpropionic acid tert-butylester (1.83 g, 5.0 mnol) and 1-bromo-2-octyne (0.95 g, 5.0 =nnol), 1.80g of the product was isolated. Yield 56%; yellowish gum; MS: 474.3(M+H)⁺.

2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyldecfynoic acid wasprepared according to the method as outlined in Example 70. Startingfrom 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec ynoic acidtert-butyl ester (1.80 g, 3.8 mmol), 1.40 g of the product was isolated.Yield 88%; off-white solid; mp 123-124° C.; MS: 416.3 (M−H)⁻.

2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-yhmethyl-decwynoic acidhydroxyide was prepared according to the method as outlined inExample 1. Staaing from2-(4fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-decfynoic acid (0.67 g,1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.22 g ofthe product was isolated. Yield 29%; white solid; mp 180-182° C.; MS:433.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO₆) δ 0.84 (t, J=6.8 Hz, 3H),1.20-1.40 (m, 6H), 1.90-2.05 (m, 2H), 2.75 (d, J=19.9 Hz, 1H), 2.94 (d,J=19.9 Hz, 1H), 3.54 (d, J=13.7 Hz, 1H), 3.75 (d, J =13.7 Hz, 1H),7.40-7.60(m, 2H), 7.70-8.00 (m, 3H), 8.30-8.40 (m, IH), 8.70-8.80 (m,2H), 11.1 (brs, 1H); IR (KBr, cm-1): 3154m, 3105s, 3067m, 2957s, 2933s,2873m, 1690s, 1631m.

Anal. Calc'd for C₂2HsFN₂O₄S.HCl: C, 56.34; H, 5.59; N, 5.97.

Found: C, 56.18; H, 5.54; N,5.76.

EXAMPLE 78

2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynyl-hexynoic acid hydroxyamide

2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynylhexynoic acid tert-butyl esterwas prepared according to the procedure as outlined in Example 9.aSctarting from 2-(4fluoro-benzenesulfonyl)-acetic acid tert-butyl ester(4.87 g, 20 mmol) and 1-bromo-2-butyne (5.36 g, 40 mmol), 6.0 g of theproduct was isolated. Yield 77%; white solid; mp 85° C.; MS: 379.1(M+H)⁺.

2-(4-Fluoro-benzenesulfonyl)-2-but-2-yiiyl-hexynoic acid was preparedaccording to the procedure as outlined in Example 70, starting from2-(4fluoro-benzenesulfonyl)2-but-2-ynyl-hex-4-ynoic acid tert-butylester (3.50 g, 8.47 mmol), 2.35 g of the product was isolated. Yield 79%; white solid; mp 129-131° C.; MS: 642.8 (2M−H)⁻.

2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex4ynoic acid hydroxyamidewas prepared according to the method as outlined in Example 1. Startingfrom 2-(4-fluoro-benzenesulfonyl)-2-but-2-ynyl-hex4-ynoic acid (0.26 g,0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmnol), 0.21 g ofthe product was isolated. Yield 77%; white solid; mp 161-163° C.;MS:338.1(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) o 1.67(s, 6H), 2.80-3.10 (m,4H), 7.51 (dd, J=9.0, 9.0 Hz, 2H), 7.87 (m, 2H), 9.26 (brs, 1H), 10.95(brs, 1H); IR (KBr, cm-1): 3336s, 3245r, 168 Is, 1589m, 1493m;

Anal. Calc'd for C₁₆H₁₆FNO₄S: C, 56.96; H, 4.78; N, 4.15.

Found: C, 56.59; H, 4.75; N, 4.04.

EXAMPLE 79

2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hexenoicacid hydroxyamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hexAenoicacid ethyl ester was prepared, starting from (5.0 g, 20 mmol)2-(4methoxy-benzenesulfonyl)-acetic acid ethyl ester and isoprenylbromide (6.0 g, 40 mmol). Yield 7.0 g, 88%; Colorless oil; MS: 395(M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoicacid ethyl ester (3.5 g, 9 mmol), 3.3 g (97%) of2-(4methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoicacid was isolated as a colorless oil by following the procedure asoutlined in Example 9. MS: 365 (M−H)⁻.

Starting from2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hexenoicacid (2.6 g, 7.0 mmol) and following the procedure as outlined inExample 1, 1.36 g of2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoicacid hydroxyamide was isolated as a colorless solid. Yield: 67%; mp93-96° C.; Ms: 393 (M+H)+; ¹H NMR (300 MHz, CDCl₃): δ 1.68 (s, 6H), 1.73(s, 6H), 2.72 (m, 4H), 3.82 (s, 3H), 5.12 (m, 2H), 6.92 (d, J=8 Hz, 2H),7.33 (bs, 1H), 7.72 (d, J=8 Hz, 2H), 9.71 (bs, 1H).

EXAMPLE 80

2-(4-methoxy-phenylsulfanyl)-heptanoic acid hydroxyamide.

2-(4-Methoxy-phenylsulfanyl)-heptanoic acid ethyl ester (13.8 g, 98%)was prepared according to the general method as outlined in example 1starting from ethyl 2-bromoheptanoate (11 g, 47 mmol) and4methoxythiophenol (6 g, 42.8 mmol), as a yellow oil; MS: 297.2 (M+H)⁺.

2-(4-Methoxy-phenylsulfanyl)-heptanoic acid was prepared starting with2-(4-methoxy-phenylsulfanyl)-heptanoic acid ethyl ester (4 g, 13.5 mmol)dissolved in methanol (300 ml) and 10 N NaOH (25 ml). The resultingreaction mixture was worked up as outlined in example 1. Yield 3 g(83%). yellow oil. MS: 267.1 (M−H)⁻.

Starting from 2-(4-methoxy-phenylsulfanyl)-heptanoic acid (2.49 g, 9.32mmol) and following the procedure as outlined in example 1, 1.83 g of2-4-(methoxy-phenylsulfanyl)-heptanoic acid hydroxyamide was isolated asan off white solid Mp 90-95° C.; Yield 70%; MS: 284.0 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆): δ 0.826 (t, J=6.9 Hz, 3H), 1.135-1.76 (m, 8H), 3.35(m, 1H), 3.82 (s, 3H), 6.91-7.49 (m, 4H).

EXAMPLE 81

(49A) 2R*-(4-methoxy-phenyl-S*-sulfnyl)-heptanoic acid hydroxyamide and

(49B) 2S*-(4-methoxy-phenyl-R*-sulfinyl)-heptanoic acid hydroxyamide

Starting from 2-(4-methoxy-phenylsulfanyl)-heptanoic acid hydroxyamide(1.69 g, 6 mmol) and following the procedure outlined in example 5, thetwo diastereomers of 2-(4-methoxy-phenylsulfanyl)-heptanoic acidhydroxyamide were separated on a silica gel column using 75% ethylacetate:hexanes. The less polar isomer,2R*-(4-methoxy-phenyI-S*-sulfiryl)-heptanoic acid hydroxyamide wasisolated as a white powder. Yield: 390 mg (22%); mp 115° C.; MS: 300.0(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 0.828 (t, J=6.2 Hz, 3H), 1.18-1.23(m, 6H), 1.73-1.99 (m, 2H), 3.11-3.15 (m, 1H), 3.82 (s, 3H), 7:09-7.61(m, 4H). The more polar isomer,2S*-(4-methoxy-phenyl-R*-sulfmyl)-heptanoic acid hydroxyamide wasisolated as a gray solid. Yield: 200 mg (11%); mp 112° C.; MS: 300.0(M+H)⁺,¹H NMR (300 MHz, DMSO-d₆): δ 0.754 (t, J=6.9 Hz, 3H), 1.014-1.121(m, 6H), 1.58-1.89 (m, 2H), 3.10-3.15 (m, 1H), 3.834 (s, 3H), 7.13-7.65(m, 4H).

EXAMPLE 82

2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholinyl-ethoxy)-phenyl]-propionichydroxyamide hydrochloride.

Following the procedure as outlined in example 12,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester was prepared, starting from (4.0 g, 15 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and4-(morpholin-1-yl-ethoxy)-benzyl chloride hydrochloride (2.9 g, 10mmol). Yield 4.8 g, 98%; Brown oil; MS: 492 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4(2-morpholin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester (4.0 gm, 8.1 mmol) 3.2 g (Yield: 84 %) of2-(4methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-1-yl-ethoxy)-phenyl]-propionicacid was isolated as colorless crystals by following the procedure asoutlined in example 9. Mp 171° C.; MS: 464 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4(2i-morpholin-1-yl-ethoxy)-phenyl]-propionicacid (4.0 g, 8.6 mmol) and following the procedure as outlined inexample 1, 2.5 g of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-1-yl-ethoxy)-phenyl]-propionichydroxyamide was isolated as colorless solid. The hydrochloride salt wasprepared by reacting the free base with methanolic hydrogen chloride at0° C. Yield: 2.5 g, 60%; mp 98° C.; MS: 479 (M+H)⁺; ¹H NlvR (300 Mdz,CDCl₃): 1.36 (s, 3H), 3.8 -12.6 (m, 16 H), 3.9 (s, 3H), 4.1-4.3 (m, 1H),6.6 (d, J=8 Hz, 2H), 6.96 (d, J=9 Hz, 2H), 7.1 (d, 8 Hz, 2H), 7.84 (d, 9Hz, 2H), 10.8 (bs, 1H).

EXAMPLE 83

1-Benzyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4carboxylic Acidhydroxyamide

To a stirred solution of 4-methoxybenzenethiol (2.8 gin, 20 miol) andanhydrous K₂CO₃ (10 gm, excess) in dry acetone (100 ml), α-bromo ethylacetate (3.3 gm, 20 mmol) was added in a round bottom flask and thereaction mixture was heated at reflux for 8 hours with good stirring. Atthe end, the reaction mixture was allowed to cool and the potassiumsalts were filtered off and the reaction mixture was concentrated. Theresidue was extracted with chloroform and washed with H₂O and 0.5 N NaOHsolution. The organic layer was her washed well with water, dried overMgSO₄, filtered and concentrated. (4-methoxy-phenylsulfanyl)-aceticacetic acid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g(100%), MS; 227 (M+H)⁺.

To a stirred solution of 60% 3-chloroperoxybenzoic acid (14.0 gm, 40mmol) in methylene chloride (100 ml) at 0° C.,(4-methoxy-phenylsulfany1)-acetic acid ethyl ester (4.4 g, 20 mmol) inCH₂Cl₂ (15 ml) was added slowly. The reaction mixture turned cloudy andwas stirrd at room temperature for 6 hours. The reaction mixture wasthen diluted with hexanes (300 ml) and stirred for 15 minutes. Thesolids were filtered off and Na₂SO₃ solution was added to the organiclayer which was stirred for at least 3 hours before the mixture wasextracted with CHCl₃ and washed with H₂O. The organic layer was driedover MgSO₄, filtered and concentrated and the colorless(4-methoxy-phenylsulfonyl)-acetic acid ethyl ester was isolated as anoil. Yield: 100%; MS: 259.1 (M+H)⁺.

To a stirred solution of diethanol armine (10.5 g,100 mmol), andanhydrous K,)CO₃ (30 gm, excess) in dry acetone (250 ml), benzyl bromide(17.2 gm, 100 mmnol) was added in a round is bottom flask and thereaction mixture was heated at reflux for 8 hours with good stirring. Atthe end, the reaction mixture was allowed to cool and the potassiumsalts were filtered off and the reaction mixture was concentrated. Theresidue was extracted with chloroform and washed with H₂O. The organiclayer was fuirther washed well with water, dried over MaSO₄, filteredand concentrated. Colorless oil. Yield: 19.0 g,97%; MS: 196 (M+H).

N-B enzyldiethanolarnine (9.75 g,50 mmol) was dissolved in saturatedmethanolic hydrochloric acid and concentrated to dryness. Thehydrocltloride thus formed was dissolved in methylene chloride (300 ml)and thionyl chloride (20 g, excess) was added dropwise and stirred atroom temperature for I hr. At the end reaction mixture was concentratedto dryness and the product bis-(2-chloroethyl)-benzyl aminehydrochloride wasp used for further transformation with out anypurification. Yield: 13.0 g, 97%; Mp: MS: 232 (M+H).

To a stirred solution of bis-(2-chloro-ethyl)-benzyl amine hydrochloride(6.6 g, 24.7 mmol), 18-Crown-6 (500 mg), and anhydrous K₂CO₃ (30 gmn,excess) in dry acetone (250 ml), (4-methoxy-phenylsulfonyl)-acetic acidethyl ester (6.12 gm, 24 mmol) was added in a round bottom flask and thereaction mixture was heated at reflux for 16 hours with good stirig. Atthe end, the reaction miixture was allowed to cool and the potassiumsalts were filtered off and the reaction mixture was concentrated. Theresidue was extracted with chloroform and washed with H₂O. The organiclayer was furher washed well with water, dried over MgSO₄, fitered andconcentrated. The dark brown reaction mixture was purified by silica gelcouinn chromatography by eluting it with 30% ethylace tate: hexane andthe product4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acidethyl ester was isolated as Brown oil. Yield: 6.0 g, 60%; MS: 418 (M+H).

4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acidethyl ester (5.0 g, 11.9 mmnol) was dissolved in MeOHTHF (1:1, 200 ml)and stirred at room temperature for 72 hrs. At the end reaction mixturewas concentrated and the product was nuetralised with con. Hcl bydissolving it in water (200 ml). After the nuetralition reaction mixturewas concentrated to dryness. Ice cold water (100 ml) was added to thesolid and filtered. The product4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid wasdried at 50 C and taken to next step with out any purification.Colorless solid Yield: 3.2 g, 69% ; MS: 390 (M+H).

To a stirred solution of4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid (2.0g, 5.1 mmol) and DMF (2 drops) in CH₂Cl₂ (100 ml) at OC, oxalyl chloride(1.0 gm, 8 mmol) was added in a drop-wise manner. After the addition,the reaction mixture was stirred at room temperature for 1 hour.Simultaneously, in a separate flask a mixture of hydroxylaininehydrochloride (2.0 gm, 29 mmol) and triethylamine (5 ml, excess) wasstirred in THF:water (5:1, 30 ml) at 0° C. for 1 hour. At the end of 1hour, the oxalyl chloride reaction mixture was concentrated and the paleyellow residue was dissolved in 10 ml of CH₂Cl₂ and added slowly to thehydroxylamine at 0° C. The reaction mixture was stirred at roomtemperature for 24 hours and concentrated. The residue obtained wasextracted with chloroform and washed well with water. The productobtained was purified by silica gel column chromatography and elutedwith chloroform the product4-(4-Methoxy-benzenesulfonyl)-l-benzyl-piperidinefcarboxylic acidhydroxyamide was isolated as a colorless solid. mp 90-95° C.; Yield, 1.2g, 48%; MS: 405 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 8 2.29 (m, 3H),2.76-2.79 (m, 2H), 3.43 (m, 4H),4.30 (s, 2H), 7.14-7.17 (d,2H),7.50-7.73 (m, 5H), 9.37 (s,lH), 10.53 (s,lH), 11.18 (s,1H).

EXAMPLE 84

4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carloxylicacid hydroxyamide

2-[(2-Hydroxy-ethyl)-(3-methoxy-benzyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine ( 3.1 g, 29.5 mmol) and 3-methoxybenzyl chloride (5 g,31.9 mmol). Yield 9.28 g, (99 %); yellow oil; MS: 226 (M+H).

3-Methoxybenzyl-bis-(2-chloro-ethyl)-amine was prepared according to thegeneral method as outlined in example 83. Starting from 3-Methoxy-benzyldiethanolamine (4.4 g, 20 mmol). Yield 4.5 g (93 %); yellow solid mp86-88 C; MS: 263. (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(3-methoxy-benzy1)piperidinecarboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-aceticacid ethyl ester (5.0 g, 22 mmol) and bis- (2-chloroethyl)-(3-methoxy-benzyl)-amine (8.0 g, 23.5 mmol). Yield 2.4 g (24 %);low melting solid; MS: 447.9 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)1-(3-methoxy-benzyl)-piperidine4carboxylicacid was prepared starting from4-(4-Methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)piperidine-4-carboxylicacid ethyl ester (2.4g, 5.36 mmol) dissolve in methanol (30 mL), 10 Nsodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resultingreaction mixture was worked up as outlined in example 83. Yield 710 mg(32%). white solid mp 199° C., MS: 419.9 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid (830 mg, 1.98 mmol) and following the procedure as outlined inexample 83, 190 mg of4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxamide was isolated as a white solid. mp 130° C.; Yield 20.4%;MS: 435.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 2.24-2.32(m, 2H), 2.51(d,2H), 2.73-2.83 (m, 2H), 3.37 (d, 2H), 3.76 (s, 3H), 3.88 (s, 3H), 4.32(s, 2H), 7.01-7.77 (m,8H), 9.38 (s, 1H0, 10.1 (s, 1H).

EXAMPLE 85

1-(3,4-dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxamide

2-[(2-Hydroxy-ethyl)-(3,4-dichloro-benzyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Stariing fromdiethanolamine (4.84 g, 46 mmol) and 3,4-dichlorobenzyl chloride (9.0 g,46 mmol). Yield 13.8 g (99 %); colorless oil; MS: 264.3 (M+H)⁺.

3,4-Dichlorobenzyl-bis-(2-chloro-ethyl)-amine was prepared according tothe general method s as outlined in example 83. Starting from3,4-dichiorobenzyl diethanolamine (10.7 g, 41 mmol). Yield 99%; yellowsolid mp 218-220° C.; MS: 301.8 (M+H)⁺.

1-(3,4-Dichloro-benzyl)4-(methoxy-benzenesulfonyl)-piperidinecarboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from4-(methoxy-benzenesulfony-1)-acetic acid ethyl ester (2.9 g, 11 mmol)and 3,Sdichlorobenzy1-bis(2-chloroethyl)-amine (3.4 g, 11 mmol). Yield5.9 g (60 %); brown oil; MS: 494.5 (M+H)⁺.

1-(3,4-Dicoro-benzyl)-4-(4-methoxy-benzenesulfulfonyl)-piperidine-4-carboxylicacid was prepared starting from1-(3,4-dichloro-benzyl)-4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester (5.0 g, 10 mmol) dissolved in methanol (50 mL), 10 Nsodium hydroxide (15 mL) and tetrahydrofuran (75 mL). The resultingreaction mixture was worked up as outlined in example 83. Yield 2.94 g(62%), MS: 458.3 (M+H)⁺.

Starting from1-(3,4-dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid (2.67g, 5.8 mmol) and following the procedure as outlined inexample 83, .2 g of 1-(3,4-dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxamidewas isolated as a white solid. mp 192-195° C.; Yield 10%; MS 472.9(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 2.20-2.28 (m, 2H), 2.76-2.79 (m,2H), 3.43-3.44 (m, 4H), 4.30 (s, 2H), 7.14-7.17 (d, J=0.030, 2H),7.50-7.73 (d, J=0.02,7, 1H), 7.65-7.68 (d, J=0.029, 2H), 7.72-7.75 (d,J=0.027, 2H), 7.87 (s, 1H), 9.37 (s, IH), 10.53 (s, 1H), 11.18 (s, 1H).

EXAMPLE 86

4-(4-methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide

2-[(2-Hydroxy-ethyl)-(4-methyl-benzyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Staring fromdiethanolamine (4.8 g, 46 mmol) and 4-methylbenzyl chloride (8.5 g, 46mmol). Yield 9.8 g (99%); MS: 209.9 (M+H)⁺.

4-Methylbenzyl-bis-(2-chloro-ethyl)-amine was prepared according to thegeneral method as outlined in example 83. Starting from 4-methyl-benzyldiethanolamine (6 g, 20 mmol). Yield 5.2 g (84 %); yellow solid mp145-147° C.; MS: 245.9 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(4-methyl-benzyl)piperidine4carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-aceticacid ethyl ester (7.0 g, 27 mmol) and4-methyl-bis-(2-chloro-ethyl)-amine (5.0 g, 17 mmol). Yield 4.64 g(63%); low melting solid; MS: 431.9 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)1-(4-methyl-benzyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-methoxy-benzenesulfonyl)-piperidine4carboxylic acid ethyl ester(4.3 g, 9.9 mmol) dissolve in methanol (30 mL), 10 N sodium hydroxide(10 mL), tetrahydrohydrofiran (20 mL). The resulting reaction mixturewas worked up as outlined in example 83. Yield 1.6 g (40%). white solidmp 207-208° C., MS: 404.3 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid (1.59 g, 3.9 mmol) and following the procedure as outlined inexample 83, .505 g of4-(4-methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide was isolated as a white solid. mp 176-177° C.; Yield32%; MS: 419.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 2.24-2.32 (m, 2H),2.51(t, 3H), 2.73-2.90 (m, 2H), 3.35-3.50 (m, 4H), 3.87 (s, 3H), 4.24(s, 2H), 7.13-7.17 (d, J=.039, 2H), 7.,3-7.60 (d, J=.036, 2H), 7.38-7.41(d, J=0.025, 2H), 7.65-7.68 (d, J=0.039, 2H).

EXAMPLE 87

4-(4-methoxy-benzene-sulfonyl)-1-napthalene-2-yl-methylpiperidine-4-carboxylicacid hydroxamide

2-[(2-Hydroxy-ethyl)-(2-napthyl-2-ylmethyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine (6.18 g, 59 mmol) and 2-(bromomethyl)napthalene (10 g, 45mmol). Yield 12.7 g (96 %); yellow solid mp 162-164° C.; MS: 246.0(M+H)⁺.

2-Napthyl-2-ylmethyl-bis-(2-chloro-ethyl)-anmine was prepared accordingto the general method as outlined in example 83. Starting from2-napthyl-ylmethyl-diethanol amine (10 g, 36 mmol). Yield 9.1 g (79%);brown solid mp 124-126° C.; MS: 281.9 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-napthalene-ylmethyl-piperiddine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Stang from 4-(methoxy-benzenesulfonyl)-aceticacid ethyl ester (8.4 g, 32 mmol) and 1-napdialene-ylmethylbis-(2-chloro-ethyl)-amine ((8.6 g, 27 mmol). Yield 6.5 g (52 %); lowmelting solid; MS: 440.0 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-napthalene-ylmethyl-piperidine-4-carboxylicacid was prepared starting from4-(4-methoxy-benzenesuIfonyl)-napthalene-ylmethyl-piperidine-4-carboxylicacid ethyl ester (6.3g, 13 mmol) dissolved in methanol (30 mL), 10 Nsodium hydroxide (30 mL) and tetrahydrofuran (30 mL). The resultingreaction miixture was worked up as outlined in example 83. Yield 2.3 g(36%). yellow solid mp 226-228° C., MS: 440.0 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-napthalene-2-yl-methylpiperidine-4-carboxylicacid (2.18g, 5.0 mmol) and following the procedure as outlined inexample 83, .753 g of4-(4-methoxy-benzene-sulfonyl)-1-napthalene-2-yl-methylpiperidine-4-carboxylicacid hydroxamide was isolated as a off white solid. mp 168-170° C.;Yield 31%; MS 455.0 (M+H)⁺; H NMR (300 MHz, DMSO-d₆): δ 2.29-2.33 (m,2H), 2.86-2.89 (m, 2H), 3.42-3.46 (m, 4H), 3.85 (s, 3H), 4.46 (s, 2H),7.13-7.16 (d, J=0.030, 2H), 7.56-7.64 (m, 3H), 7.65-7.68 (d, J=0.030,2H), 7.98-8.00 (m, 3H), 8.21 (s, 1H), 10.70 (s, 1H), 11.20 (s, 1H).

EXAMPLE 88

1-Biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylicacid hydroxamide

2-[(2-Hydroxy-ethyl)-(1-biphenylfylmethyl))-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanol amine (5.2 g, 49 mmol) and 4-(chloromethyl)biphenyl (10 g, 49mmol). Yield 9.98 g (66 %); white solid mp 160-162° C.; MS: 271.9(M+H)⁺. This was converted to the dichloride as outlined in example 83

1-Biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-aceticacid ethyl ester (2.85 g, 11 mmol) andl-biphenyl4-ylmethyl-bis-(2chloro-ethyl)-amine (3.4 g, 11 mmol). Yield2.1 g, (39 %); beige solid, mp 176-178° C., MS: 494.1 (M+H)⁺.

1-Biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid was prepared starting from1-biphenyl-4-ylmethyl-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester (5.7g, 12 mmol) dissolved in ethanol (20 mL),tetrahydrofuran (20 mL) and 10 N sodium hydroxide (10 mL). The resultingreaction mixture was worked up as outlined in example 83. Yield 2.1g(39% ) MS: 465.8 (M+H)⁺.

Starting from 1-biphenyl-4-ylmethyl-4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid (1.0 g, 2.2 mmol and following the procedure as outlined in example83, .132g of1-biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylicacid hydroxamide was isolated as a tan solid. mp168° C.; Yield 20%; MS:440.9 (M+H)⁺; ¹H NMR (300 ML, DMSO-d₆): δ 2.30-2.35 (m, 2H), 2.83-2.87(m, 2H), 3.35-3.5 (m, 4H), 3.87 (s, 3H), 7.15-7.721 (d, J=0.059 Hz, 2H),7.49-7.65 (m, 5H), 7.68-7.74(d, J=.06 Hz, 2H), 9.3 (s, 1H), 10.3 (s,1H), 11.15 (s, 1H).

EXAMPLE 89

4-(4-methoxy-benzene-sulfonyl)-1-(3-methyl-but-2-enyl)piperidine4carboxylicacid hydroxamide

2-[(2-Hydroxy-ethyl)-1-(3-methyl-but-2-enyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanol amine (4.1 g, 39 mmol) and 4-bromo-2-methyl-butene (6.0 g, 40mmol). Yield ( 98 %); brown oil; MS: 173.8 (M+H)⁺.

1-(3-methyl-but-2-enyl)]-bis-(2-chloro-ethyl)-amine was preparedaccording to the general method as outlined in example 83. Starting from2-[(2-hydroxy-ethyl)-1-(3-methyl-but-2-enyl)-amino]-ethanol (10.4g, 50mmol). Yield 10.5g (99%); brown solid; MS: 210.3 (M+H)

4(4-Methoxy-benzenesulfonyl)-1-(3-methyl-but-2enyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 1. Starting from 4-(methoxy-benzenesulfonyl)-aceticacid ethyl ester (11.32 g, 44 mmol) and3-methyl-but-2-enyl)-bis-(2-chloroethyI)-amme ( 10.4 g, 50 mmol). Yield6.2 g (36 %); brown oil; MS: 395.6 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)piperidine-4-carboxylicacid was prepared starting from4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylicacid ethyl ester (6.2g, 16 mmol) dissolved in ethanol (15 mL), 10 Nsodium hydroxide (10 mL) and tetahydrofuiran (75 mL). The resultingreaction mixture was worked up as outlined in example 83. Yield 1.2 g(21%). brown solid mp 196-197 ° C, MS: 367.9 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylicacid (1.0 g. 3.0 mmol) and following the procedure as outlined inexample 83, .110 mg of4-(4-methoxy-benzene-sulfonyl)-1-(3-methyl-but-2-enyl)piperidine-4-carboxylicacid hydroxamide was isolated as a yellow solid. mp 142-145° C.; Yield12%; MS: 382.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.67 (s, 3H), 1.79(s, 3H), 2.18-2.23 (m, 2H), 2.66-2.73 (m, 2 H), 3.37-3.46 (m, 2H),3.67-3.69 (m, 2H), 5.19-5.24 (m, 1H), 7.15-7.18 (d, J=0.03, 2H),7.67-7.70 (d, J=0.030, 2H), 9.34 (s, 1H), 9.88 (s, IH),.11.15 (s, 1H).

EXAMPLE 90

1-(Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide

2-[(4-Bromobenzyl)-(2-hydroxy-ethyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine (22.5 g, 150 mnmol). and 4-bromobenzyl bromide (25 g, 100mmol). Yield 33.66g, (99%); yellow oil; MS: 273.8 (M+H)⁺.

(4-Bromo-benzyl)-bis-(2-chloro-ethyl)-amine was prepared according tothe general method as outlined in example 83. Starting from2-[(4-bromobenzyl)-(2-hydroxy-ethyl)-amino]-ethanol (33.28 g, 122 mmol).Yield 47 g, (99%); brown solid; mp 125 ° C; MS: 309.8 (M+H)⁺.

1-(4-Bromo-benzyl)-4-(4methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Staring from 4- (methoxy-benzenesulfonyl) aceticacid ethyl ester (8.6 g, 33.5 mmol) and(4-bromobenzyl)-bis-(2-chloroethyl)-amine (13.3 g, 38.6 mmol). Yield 17g (44%); brown oil; MS: 497.8 (M+H)⁺.

1-(4-Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid was prepared starting from1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester (16.5 g, 33.3 mmol) dissolved in TBF:methanol 3:1 and10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 6.18 g (40%); tan solid; mp 215° C.; MS:469.7 (M+H)⁺.

Starting from1-(4-Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid (1.95 g, 4.2 mmol) and folowing the procedure as outlined inexample 83, 1.29 g of1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 60%; mp 180°C.; MS: 484.7 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 2.18-2.29 (m, 2H),2.46 (d, 2H), 2.74-2.89 (m, 2H), 3.39 (d, 2H), 3.87 (s, 3H), 4.28 (s,2H), 7.18 (d, J=17 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.65-7.68 (m, 4H),9.37 (s, 1H), 10.5 (s, 1H).

EXAMPLE 91

4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylicacid hydroxyamide

2-[(2-Hydroxy-ethyl)-(3-phenyl-propyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine (15.8 g, 151 mmol). and 1-bromo-3-phenylpropane (20 g,101 mmol). Yield 21.31 g, (95%); yellow oil; MS: 223.9 (M+H)⁺.

Bis-(2-Chloro-ethyl)-(3-phenyl-propyl)-amine was prepared according tothe general method as outlined in example 83. Starting from2-[(2-hydroxy-ethyl)-(3-phenyl-propyl)-amino]-ethanol (20.32 g, 90.7mmol). Yield 24.9 g (92%); brown oil; MS: 259.8 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (12 g, 46.5 mmol) andbis-(2-chloro-ethyl)-(3-phenyl-propyl)-amine (24.8 g, 93.8 mmol). Yield11.24 g (54%); brown oil; MS: 446 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-Methoxy-benzenesulfonyl)-1(3-phenyl-propyl)-piperidine-4-carboxylicacid ethyl ester (10.74 g, 24.13 mmol) dissolved in THF:methanol 3:1 and10 N NaOH (40 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 4.67 g (47%); off white powder, mp 203°C.; MS: 418.2 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylicacid (4.37 g, 10.4 mmol) and following the procedure as outlined inexample 83, 1.64 g of4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 37%; mp 143°C.; MS: 432.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.92-1.97 (m, 2H),2.18-2.29 (m, 2H), 2.47 (d, 2H), 2.58 (t, J=7.7 Hz, 2H), 2.6-2.73 (m,2H), 3.0-3.06 (m, 2H), 3.60 (d, J =12.3 Hz, 2H), 3.87 (s, 2H), 7.15-7.30(m, 7 H), 7.68, (d, J=9 Hz, 2H), 9.3 (s, 1H), 10.1 (s, 1H).

EXAMPLE 92

1-Tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide

tert-Butyl-bis-(2-chloroethyl)-amine was prepared according to thegeneral method as outlined in example 83. Starting from1-tert-butyl-diethanolamine (6 g, 37.2 mmol). Yield 11.15 g, (99%);white solid; MS: 197.8 (M+H)⁺.

1-tert-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester was prepared according to the general method as outlined inexample 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethylester (10 g, 38.76 mmol) and tert-butyl-bis-(2-chloro-ethyl)-amine (5.25g, 22.53 mmol). Yield 5.37 g, (62%); brown oil; MS: 384 (M+H)⁺.

1-tert-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidwas prepared starting from1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester (5.37 g 14 mmol) dissolved in methanol (300 ml) and 10 NNaOH (23 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 1.52 g (30.6%); white powder; mp 204° C.; MS: 356(M+H)⁺.

Starting from1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid(320 mg, 0.9 mmol) and following the procedure as outlined in example83, 190 mg of1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide was isolated as a green solid. Yield 52%; mp 40° C.; MS:371.1 (M+H)⁺; ¹H NMR (300 Mz, DMSO d): δ 1.29 (s, 9H), 1.54 (m, 2H),1.66 (m, 2H), 2.39 (m, 2H), 2.98 (m, 2H), 3.88 (s, 3H), 7.18 (d, 2H),7.67 (d, 2H).

EXAMPLE 93

1-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide

Butyl-bis-(2-chloro-ethyl)-amine was prepared according to the generalmethod as outlined in example 83. Starting from N-butyldiethanolamine (6g, 37.2 mmol). Yield 11.3 g, (99%); white powder; mp 165° C.; MS: 197.9(M+H)⁺.

1-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester was prepared according to the general method as outlined inexample 83. Startng from 4-(methoxy-benzenesulfonyl) acetic acid ethylester (5 g, 19.38 mmol) and butyl-bis-(2-chloroethyl)-amine (4.52 g,19.38 mmol). Yield 6.86 g, (93%); brown oil; MS: 384 (M+H)⁺.

1-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid wasprepared starting from1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester (6.42 g 16.8 mmol) dissolved in methanol (200 ml) and 10 N NaOH(20 ml). The resulting reaction mixture was worked up as outlined inexample 83. Yield 1.6 g (27%); white powder; mp 206° C.; MS: 356.4(M+H)⁺.

Starting from1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (1.51g, 4.3 mmol) and following the procedure as outlined in example 83, 200mg of 1-butyl(4-methoxy-benzenesulfonyl)-piperidine4-carboxylic acidhydroxyamide was isolated as an off white solid. Yield 9.3%; mp 75° C.;MS: 371.1 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.87 (t, J=7.2 Hz, 3H),1.27 (m, 2H), 1.59 (m, 2H), 2.27 (m, 2H), 2.45 (m, 2H), 2.50 (m, 2H),2.65 (m, 2H), 2.97 (m, 2H) 3.88 (s, 3H), 7.18 (d, 2H), 7.69 (d, 2H).

EXAMPLE 94

1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide

Cyclooctyl-bis-(2-chloro-ethyl)-amine was prepared according to thegeneral method as outlined in example 83. Starting fromN-cyclooctyldiethanolamine (6 g, 28 mmnol). Yield 10 g, (99%); off whitesolid; mp 158° C.; MS: 251.9 (M+H)⁺.

1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester was prepared according to the general method as outlined inexample 83. Stting from 4-(methoxy-benzenesulfonyl) acetic acid ethylester (5 g, 19.4 mmol) and cyclooctyl-bis-(2-chloro-ethyl)-amine (5.57g, 19.4 mmol). Yield 8.2 g, (96%); brown oil; MS: 438 (M+H)⁺.

1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidwas prepared starting from1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester (8 g, 183 mmol) dissolved in methanol (200 ml) and 10 N NaOH(25 ml). The resulting reaction mixture was worked up as outlined inexample 83. Yield 2.36 g (32%); white powder; mp 180° C.; MS: 410(M+H)⁺.

Starting from1-Cyclooctyl-4-(4-methoxy-benzenesuIfonyl)-piperidine-4-carboxylic acid(2.26 g, 5.53 mmol) and following the procedure as outlined in example83, 570 mg of1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide was isolated as a white powder. Yield 22%; mp >200° C.; MS:425 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.42-1.66 (m, 14H), 1.83 (m,2H), 2.33 (m, 2H), 2.67 (m, 2H), 3.30-3.51 (m, 3H) 3.88 (s, 3H) 7.17 (d,2H), 7.66 (d, 2H).

EXAMPLE 95

1-Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide

1-Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester was prepared according to the general method as outlined inexample 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethylester (3 g, 11.6 mmol) and ethyl-bis-(2-chloro-ethyl)-amine (2.39g, 11.6mmol). Yield 3.09 g, (75%); low melting brown solid; MS: 356 (M+)⁺.

1-Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid wasprepared staring from 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidinencarboxylic acid ethylester (2.42 g, 6.8 mmol) dissolved in methanol (100 ml) and 10 N NaOH(15 ml). The resulting reaction mixture was worked up as outlined inexample 83. Yield 1.29 g (58%);- white solid; mp 209° C.; MS: 328 (+M)⁺.

Starting from1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (1.23g, 3.76 mmol) and following the procedure as outlined in example 83,1.02 g of 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white powder. Yield 80%; mp 85°C.; MS: 343 (M+H)+; ¹H NEM (300 M , DMSO d₆): δ 0.926 (t, J=7.1 Hz, 3H),1.68-1.89 (m, 4H), 2.05-2.24 (ne, 4H), 2.73 (q, 2H), 3.85 (s, 3H), 7.07(d, 2H), 7.64 (d, 2H).

EXAMPLE 96

1-Isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide

1-Isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester was prepared according to the general method as outlined inexample 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethylester (5.7 g, 22.2 mmol) and isopropyl-bis-(2-chloro-ethyl)-amine (4.9g, 22.2 mmol). Yield 5.64 g, (68%); low melting brown solid; MS: 370(M+H)⁺.

1-Isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4 -carboxylic acidwas prepared starting from1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester (5.6 g, 15.2 mmol) dissolved in methanol (75 ml) and 10 NNaOH (25 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 2.18 g (42%); white powder; mp 204° C.; MS: 341.9(M+H)⁺.

Starting from1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4carboxylic acid(2.13 g, 6.25 mmol) and following the procedure as outlined in example83, 590 mg of1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide was isolated as a white powder. Yield 2.4%; mp 75° C.; MS:357 (M+H)+; ¹H NMR (300 MD, DMSO-d₆): δ 1.21 (d, J=6.6 Hz, 611),2.33-3.53 (m, 9H), 3.88 (s, 3H), 7.16 (d, 2H), 7.66 (d, 2H).

EXAMPLE 97

1-Methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyaride

1-Methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester was prepared according to the general method as outlined inexample 83. Starting from 4(methoxy-benzenesulfonyl) acetic acid ethylester (3 g, 11.6 mmol) and methyl-bis-(2-chloro-ethyl)-amine (2.2g, 11.6mmol). Yield 3.09 g, (75%); low melting brown solid; MS: 342 (M+H)⁺.

1-Methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4 -carboxylic acid wasprepared starting from1-methyl-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester (8.7 g, 25.6 mmol) dissolved in methanol (300 ml) and 10 N NaOH(35 ml). The resulting reaction mixture was worked up as outlined inexample 83. Yield 3.23 g (41%); white solid; mp 204° C.; MS: 313.9(M+H)⁺.

Starting from1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (2.0g, 6.38 mmol) and following the procedure as outlined in example 83, 1.10 g of 1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as a yellow powder. Yield 53%; mp 89° C.;MS: 329 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.67-1.76 (m, 2H),1.85-1.96 (m, 2H), 2.05 (s, 3H), 2.17 (d, J3=11.4 Hz, 2H), 2.57 (d,J=10.4 Hz, 2H) 3.83 (s, 3H), 7.02 (d, 2H), 7.62 (d, 2H).

EXAMPLE 98

1-Benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide

1-Benzyl-4-(butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester was prepared according to the general method as outlined inexample 83. Starting from from 4-(butoxy-benzenesulfonyl) acetic acidethyl ester (6 g, 20 mmol) and bis-(2-chloro-ethyl)-benzylamine (10 g,30 mmol). Yield 5.15 g (56%); yellow oil; MS: 460 (M+H)⁺.

1-Benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid wasprepared starting from1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester (5.1 g, 11.1 mmol) dissolved in TBF:methanol 3:1 and 10 N NaOH (10ml). The resulting reaction mixture was worked up as outlined in example83. Yield 2.66 g (56%); off white solid; mp 210° C.; MS: 432 (M+H)⁺.

Starting from1-benzyl-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (2.61g, 6.06 mmol) and following the procedure as outlined in example 83, 860mg of 1-benzyl-4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide was isolated as an off white powder. Yield 32%; mp 144° C.;MS: 446.9 (M+H)⁺; ¹H NMR (300 MHZ, DMSO-d₆): δ 0.94 (t, J=7.3 Hz, 3H),1.44,(q, J=7.5 Hz, 2H), 1.70 (q, 2H), 2.28-2.32 (m, 2H), 2.50 (d, 2H),2.74-2.83 (m, 2H), 3.35 (d, 2H), 4.08 (t, J =6.3 Hz, 2H), 4.34 (s, 2H),7.13 (d, J=8.7, 2H), 7.45 (s, 3H), 7.54 (s, 2H), 7.74 (d, J =8.7, 2H),9.35 (s, 1H), 10.7 (s, 1H).

EXAMPLE 99

1-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide

1-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidinecarboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) aceticacid ethyl ester (18.8 g, 72.8 mmol) and(4-fluoro-benzyl)-bis-(2-chloro-ethyl)-amine (20.8 g, 73 mmol). Yield 25g (79%); brown oil; MS: 436.9 (M+H)⁺.

1-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine4-carboxylicacid was prepared starting from1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester (17.4 g, 40 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 10.8 g (66%); colorlesssolid; mp 154° C.; MS: 408(M+H)⁺.

Starting from1-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid (8.14 g, 20 mmol) and following the procedure as outlined inexample 83, 4.3 g of1-(4-fluoro-benzyl)4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 51 %; mp176-178° C.; MS: 484.7 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 2.12-2.20(m, 2H), 2.64-2.79 (m, 2H), 3.32-3.45 (m, 4H), 3.87 (s, 3H), 4.31 (s,2H), 7.14-7.19 (d, J=17 Hz, 2H), 7.27-7.33 (d, J=8.1 Hz, 2H), 7.50-7.54(d, 2H), 7.65-7.68 (d, 2H), 9.38 (s, 1H), 9.75 (s, 1H).

EXAMPLE 100

1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide

1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(butoxy-benzenesulfonyl)acetic acid ethyl ester (6 g, 20 mmol) and(4-fluoro-benzyl)-bis-(2-chloro-ethyl)-amine (5.73 g, 20 mmol). Yield8.2 g (86%); yellow oil; MS: 478 (M+H)⁺.

1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid was prepared starting from1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperdine-4-carboxylicacid ethyl ester (4.77 g, 10 mmol) dissolved in TBF:methanol 3:1 and 10N NaOH (10 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 3.5 g (79%); off white solid; mp 114° C.; MS: 450(M+H)⁺.

Starting from1-(4-Fluoro-benyl)-4-(4-butoxy-benzenesulfonyl)-piperdine-4-carboxylicacid (2.24 g, 5.0 mmol) and following the procedure as outlined inexample 83, 200 mg of1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white powder. Yield 9%; mp 112°C.; MS: 465.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.94 (t, J=7.3 Hz,3H), 1.35-1.50 (m, 2H), 1.68-1.77 (m, 2H), 2.20-2.28 (m, 2H), 2.66-2.77(m, 2H), 3.77-3.78 (m, 4H), 4.064.10 (m, 2H), 4.19 (s, 2H), 7.14-7.19(d, J=8.7, 2H), 7.27-7.33 (d, 2H), 7.50-7.54 (d, 2H), 7.65-7.68 (d, 2H),9.34 (s, 1H), 10.55 (s, 1H).

EXAMPLE 101

4-(4-methoxy-benzenesulfonyl)-1-(4-medthoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide

2-[(2-Hydroxy-ethyl)-(4-methoxy-benzyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine (12.0 g, 114 mmol) and 4-methoxybenzyl chloride (14.2 g,100 mmol). Yield 17.5 g, (77 %); yellow oil; MS: 226 (M+H).

4-Methoxybenzyl-bis-(2-chloroethyl)-amine was prepared according to thegeneral method as outlined in example 83. Starting from 4-Methoxy-benzyldiethanolamine (10 g, 44 mmol). Yield 10 g (75 %); yellow solid mp 55 C;MS: 263.1 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-aceticacid ethyl ester (5.0 g, 20 mmol) and bis- (2-chloroethyl)-(4-methoxy-benzyl)-amine (7.0 g, 22 mmol). Yield 5.0 g (56 %);low melting solid; MS: 448.5 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-Methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylicacid ethyl ester (4.2g, 10 mmol) dissolve in methanol (30 mL), 10 Nsodium hydroxide (10 mL), tetrahydrohydrofimran (20 mL). The resultingreaction mixture was worked up as outlined in example 83. Yield 3.0 g(71 %). white solid mp 190 IC, MS: 420.4 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-pipeidine-4-carboxylicacid (2.0 g, 4.7 mmol) and following the procedure as outlined inexample 83, 1.2 g of 4(4methoxy-benzenesulfonyl)-1-(methoxy-benzyl)-piperidine-4-carboxylic acidhydroxamide was isolated as a white solid. mp 175° C. (HCl); Yield: 1.2g, 59 %; MS: 433.0 (M+H)⁺; ¹HMR (300 Mz, DMSO-d₆): δ 1.8 (m, 4H), 2.3(m,2H), 2.73 (m, 2H), 3.37 (d, 2H), 3.76 (s, 3H), 3.88 (s,3H), 6.87 ( d,2H), 7.11 (d, 2H), 7.21 (d, 2H), 7.65 (d, 2H),9.2 (bs, 1H), 10.9 (bs,1H).

EXAMPLE 102

4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylicacid hydroxyamide

2-{(2-Hydroxy-ethyl)-[2-(4-methoxy-phenyl)ethyl]-amino}-ethanol wasprepared according to the general method as outlined in example 83.Starting from diethanolamine (10.0 g, excess). and1-(2-chloroethyl)-4-methoxybenzene (8.5 g, 50 mmol). Yield 11 g, (92%);yellow oil; MS: 240 (M+H)⁺.

The corresponding dichloride,bis-(2-chloro-ethyl)-(4-methoxyphenyl-2-ethyl)-amine was preparedaccording to the general method as outlined in example 83. Starting from2-{(2-hydroxy-ethyl)-[2-(4-methoxy-phenyl)-ethyl]-amino}-ethanol (10 g,41.8 mmol). Yield 11 g (95%); brown oil; MS: 277.2 (M+H)⁺.

4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (5.0 g, 20 mmol) andbis-(2-chloro-ethyl)-(4-methoxyphenyl-2-ethyl)-amine (6.4 g, 20 mmol).Yield 6.0 g (65%); brown oil; MS: 462.5 (M+H)⁺.

4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyI)-ethyII-piperidine-4-carboxyIic acid was preparedstarting from4-(4methoxy-benzenesulfonyl)-1-[2-(4methoxyphenyl)-ethyl]-piperidine-4-carboxylicacid ethyl ester (5.0, 10.8 mmol) dissolved in THF:methanol 3:1 and 10 NNaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 4.0 g (85%o); off white powder; mp 205 ° C; MS:434.5 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylicacid (1.5 g, 3.46 mmol) and following the procedure as outlined inexample 83, 900 mg of4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidirne-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 58%; mp 206°C. (HCl); MS: 449.5 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 5 2.3 (m, 2H),2.5 (m, 3H), 2.8 (m, 2H), 2.95 (m, 2H), 3.25 (m, 2H), 3.4 (m,4H), 3.60(d, J =12.3 Hz, 2H), 3.77 (s, 3H),3.99 (s, 3H), 6.9 (d, 2H), 7.1-7.25,(q, 4H), 7.7 (d, 2H), 9.3 (s, 1H), 10.6 (s, 1H).

EXAMPLE 103

4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylicacid hydroxyamide

2-[(2-Hydroxy-ethyl)-(2-phenyl-ethyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 1. Starting fromdiethanolamine (6.0 g, 57). and 2-bromo-ethylbenzene (9.0 g, 48.3 mmol).Yield 9 g, (90%); yellow oil; MS: 210 (M+H)⁺.

Bis-(2-Chloro-ethyl)-(2-phenyi-ethyl)-anine was prepared according tothe general method as outlined in example 83. Starting from2-[(2-Hydroxy-ethyl)-(2-phenyl-ethyl)-amino]-ethanol (8.5 g, 40.6 mmol).Yield 11 g (95%); brown oil; MS: 247.1 (M+H)⁺.

4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(nethoxy-benzenesulfonyl)acetic acid ethyl ester (5.0 g, 20 mmol) andbis-(2-chloro-ethyl)-(2-phenyl-ethyl)-amine (5.6 g, 20 mmol). Yield 5.5g (63%); brown oil; MS: 432.5 (M+H)⁺.

4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylicacid was prepared starting from4-(4methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylicacid ethyl ester (3.0 g, 6.9 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 2.0 g (72%); off white powder; mp 208° C.; MS:404.5 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylicacid (1.5 g, 3.7 mmol) and following the procedure as outlined inexample 83, 900 mg of4-(4-methoxy-benzenesulfonyl)-1-(2-phenylethyl)-piperdine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 58%; mp 205°C. (HCl); MS: 419.4 (M+H)⁺; ¹H N (300 MHz, DMSO-d₆): δ 2.3 (m, 2H), 2.5(m, 3H), 2.8 (m, 2H), 2.95 (m, 2H), 3.25 (m, 2H), 3.4 (m,4H), 3.9 (s,3H),7.22-7.8 (m, 9H), 10.6 (s, IH), 11.2 (bs, 1H).

EXAMPLE 104

4-(4-n-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperdine-4-carboxylicacid hydroxyamide

4-(4-n-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from 4(n-Butoxy-benzenesulfonyl)-aceticacid ethyl ester (2.5 g, 10 mmol) and bis- (2-chloroethyl)-(4-methoxy-benzyl)-amine (3.0 g, 10 mmol). Yield 3.5 g (71 %);low melting solid; MS: 490.5 (M+H)⁺.

4(4-n-Butoxy-benizenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylicacid ethyl ester (3.0 g, 6.1 mmol) dissolve in methanol (30 mL), 10 Nsodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resultingreaction mixture was worked up as outlined in example 83. Yield 1.5 g(53%). white solid mp 207° C., MS: 462.5 (M+H)⁺.

Starting from4-(4-n-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylicacid (1.0 g, 2.1 mmol) and following the procedure as outlined inexample 83, 1.2 g of4(4-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxamide was isolated as a white solid. mp 173° C. (HCl); Yield:800 mg, 77%; MS: 477.5 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.9 (t, 3H),1.4 (m, 2H), 1.7 (m,2H), 2.3 (m, 2H), 2.5 (m, 2H), 2.7 (m, 2H), 3.3 (m,2H), 3.5(m, 2H), 4.1 (t, 2H), 4.3 (m, 2H), 6.97 ( d, 2H), 7.14 (d, 2H),7.48 (d, 2H), 7.7 (d, 2H), 9.4 (bs, 1H), 10.9 (bs, 1H).

EXAMPLE 105

4-(4-Methoxy-benzenesulfony)-1-(3-phenoxy-propyl)-pipendine-4-carboxyllc acid hydroxyamide

2-[(2-Hydroxy-ethyl)-(3-phenoxy-propyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine (15.8 g, 151 mmol). and 3-Phenoxypropyl bromide (21.5 g,100 mmol). Yield 21.31 g, (95%); yellow oil; MS: 238.1 (M+H)⁺.

Bis-(2-Chloro-ethyl)-(3-phenoxy-propyl)-amine was prepared according tothe general method as outlined in example 83. Stariing from2-[(2-hydroxy-ethyl)-(3-phenoxy-propyl)-amlino]-ethanol (20.0 g, 84mmol). Yield 24.0 g (91%); brown oil; MS: 277.8 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (5.2 g, 20 mmol) andbis-(2chloro-ethyl)-(3-phenoxy-propyl)-amine (7.0 g, 22 mmol). Yield 6.5g (70%); brown oil; MS: 462.5 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid ethyl ester (4.2 g, 9.1 mmol) dissolved in THF:Methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mLxture was worked up as outlinedin example 83. Yield 3.0 g (75%); off white powder; mp 195° C.; MS:434.5 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid (2.5 g, 5.77 mmol) and following the procedure as outlined inexample 83, 1.2 g of4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 46%; mp 101°C.; MS: 448.5 (M+H)⁺; ¹H NMR (300 MHi, DMSO-d₆): δ 2.18 (m, 2H), 2.3 (m,2H), 2.58 (m, 2H), 2.6-2.73 (m, 2H), 3.0-3.06 (m, 2H), 3.60 (m 2H), 3.87(s, 3H), 4.01 (t, 2H), 6.9 - 7.7 (m, 9H), 9.33 (bs, 1H), 10.28 (bs, 1H).

EXAMPLE 106

4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid hydroxyamide

4-(4n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidie-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(butoxy-benzenesulfonyl)acetic acid ethyl ester (3.0 g, 10 mmol) andbis-(2-chloro-ethyl)-(3-phenoxy-propyl)-amine (3.0 g, 11 mmol). Yield4.5 g (89%); brown oil; MS: 504.6 (M+H)⁺.

4-(4n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine4-carboxylicacid ethyl ester (4.0 g, 7.9 mmol) dissolved in THF:Methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 3.0 g (79%); off white powder; mp 191° C.; MS:476.5 (M+H)⁺.

Starting from4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid (700 mg, 1.4 mmol) and following the procedure as outlined inexample 83, 300 mg of4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 43%; mp 84°C.; MS: 491.5 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.9 (t, 3H), 1.5 (m,2H),l1.8 (m, 2H), 2.18 (m, 2H), 2.3 (m, 2H), 2.58 (m, 2H), 2.6-2.73 (m,2H), 3.2 (m, 2H), 3.40 (m 6H), 3.97 (t, 2H), 4.1 (t, 2H), 6.9-7.7 (m,9H), 10.7 (bs, 1H), 11.28 (bs, 1H).

EXAMPLE 107

4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid hydroxyamide

2-[(2-Hydroxy-ethyl)-(2-phenoxy-ethyl)-aminol-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolarine (15.0 g, 150). and 2chloro-phenetol (15.6 g, 100 mmol).Yield 18 g, (80%); Colorless oil; MS: 226 (M+H)⁺.

Bis-(2-Chioro-ethyl)-(2-phenoxy-ethyl)-amine was prepared according tothe general method as outlined in example 83. Starting from2-[(2-Hydroxy-ethyl)-(2-phenoxy-ethyl)-amino]-ethanol (20.0 g, 88.8mmol). Yield 25 g (94%); brown oil; MS: 263.1 (M+H)⁺.

4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (5.0 g, 20 mmol) andbis-(2-chloro-ethyl)-(2-phenoxy-ethyl)-amine (6.0 g, 20 mnmol). Yield5.8 g (64%); brown oil; MS: 448.5 (M+H)⁺.

4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)piperidine-4-carboxylicacid was prepared starting from4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)-piperidine-4-carboxylicacid ethyl ester (5.0 g, 11.1 mmol) dissolved in T° F:methanol 3:1 and10 N NaOH (40 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 3.0 g (63%); off white powder, mp 235° C.;MS: 420.5 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid (2.5 g, 5.9 mmol) and following the procedure as outlined inexample 83, 1.3 g of4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 50%; mp168-172 ° C (HCI); MS: 435.4 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 2.3(m, 2H), 2.5 (m, 2H), 2.9 (m, 2H), 3.4 (m, 4H), 3.5 (m, 2H), 3.7 (m,2H),3.9 (s, 3H), 4.4 (m, 2H), 6.9 - 7.8 (m, 9H), 9.3 (s, 1H), 10.2 (bs, 1H),11.3 (s, 1H).

EXAMPLE 108

4-(4-n-Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid hydroxyamide

4-(4-Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (2.5 g, 10 mmol) andbis-(2-chloro-ethyl)-(2-phenoxy-ethyl)-amine (2.98 g, 10 mmol). Yield3.0 g (69%); brown oil; MS: 490.6 (M+H)⁺.

4-(4-n-Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid was prepared starting from4-(4n-butoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)-piperidine-4-carboxylicacid ethyl ester (2.5 g, 5.76 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 1.5 g (56%); off white powder; mp 204° C.; MS:462.5 (M+H)⁺.

Starting from4-(4n-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid (1.0 g, 2.16 mmol) and following the procedure as outlined inexample 83, 600 mg of4-(4-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 58%; mp 112°C. (HCl); MS: 477.4 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.942 (t, 3H),1.4 (m, 2H), 1.7 (m, 2H), 2.3 (m, 2H), 2.5 (m, 4H), 2.8 (m, 2H), 2.9-3.4(m, 4H), 3.3 (m, 4H), 4.2 (t, 2H), 4.4 (m, 2H), 6.9-7.7 (m, 9H), 9.4 (s,1H), 10.5 (bs, 1H), 11.3 (s, 1H).

EXAMPLE 109

4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid hydroxyamide

Bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-aiine wasprepared according to the general method as outlined in example 83.Starting from diethanolainine (15.0 g, 150). and4-(2-pipeddin-1-yl-ethoxy)-benzyl chloride (5.9 g, 20 mmol). Yield 5.5g, (85%); Brown semi-solid; MS: 323 (M+H)⁺.

Bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine wasprepared according to the general method as outlined in example 83.Starting from2-[(2-Hydroxy-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine (3.22 g,10 mmol). Yield 4.0 g (92%); brown semi-solid; MS: 361.1 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4(methoxy-benzenesulfonyl)acetic acid ethyl ester (5.0 g, 20 mmol) andBis-(2-chloro-ethyl)[4-(2-piperidin-1-yl-ethoxy)-benzyll-amine (8.6 g,20 mmol). Yield 6.0 g (55%); brown oil; MS: 545.7 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid was prepared startingfrom4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid ethyl ester (5.4 g, 10 mmol) dissolved in TBF:methanol 3:1 and 10 NNaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 4.0 g (77%); off white powder, mp 174° C.; MS:517.6 (M+H)⁺.

Starting from4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-ylethoxy)-benzyl]-piperidine-4-carboxylicacid (3.5 g, 6.78 mmol) and following the procedure as outlined inexample 83, 1.8 g of 4-(4-Methoxy-beenzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxy amide wasisolated as an pale yellow solid. Yield 49%; mp 114° C. (HCl); MS: 532(M+H)⁺; ¹H NMR (300 M , DMSO-dd: δ 1.41.6 (m, 411), 1.9 (m, 2H), 5 2.3(m, 2H), 2.8 (m, 2H), 3.4 (m, 4H), 3.9 (s, 3H), 4.2 (m, 1H), 6.9-7.8 (m,8H), 9.1 (s, 1H), 10.8 (bs, 1H).

EXAMPLE 110

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-propionamide

Step A: Coupling of 2-bromo-propionic acid to hydroxylamine resin.

4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin¹(2 g, 1.1 meq/g) was placed in a peptide synthesis vessel (ChemglassInc. Part Number CG-1866) and suspended in DMF (20 mL). 2-Bromopropionicacid (0.6 nL, 3.0 eq.) 1-hydroxybenzotriazole hydrate (HOBt, 1.8 g, 6.0eq.) and 1,3-diisopropylcarbodlimide (DIC, 1.4 mL, 4.0 eq.) were added.The reaction was shaken on an orbital shaker at room temperature for2-16 hours. The reaction was filtered and washed with DMF (3×20 mL). Asample of resin was removed and subjected to the Kaiser test. If thetest showed the presence of free amine (resin turned blue) the couplingdescribed above was repeated, otherwise the resin was washed with DICM(3×20 mL), MeOH (2×20 mL), and DCIM (2×20 mL). (A wash consisted ofaddition of the solvent and agitation either by nitrogen bubbling orshaking on the orbital shaker for 1-5 minutes, then filtration underv[acun). The resin was dried in vacuo at room temperature.

A sample of resin (5-20 mg) was subjected to cleavage with DCM (0.5 AL)and TFA (0.5 mL) for 1 hour at room temperature. The reaction wasfiltered and the resin washed with DCM (1×1 mL). The filtrate and thewashing were combined and concentrated in vacuo on a Savant SpeedVacPlus. Methanol (1 mL) was added and the mixture concentrated. Theproduct was then characterized by H¹NMR, (DMSO d-₆) δ 4.54 (q, 1H), 1.83(d, 3H).

Step B: Displacement of bromide with 4-methoxybenzenethiol.

The N-Hydroxy-2-bromo-propionamide resin prepared in Step A (0.35 g, 1.1meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2mL). 4-Methoxybenzenethiol (0.23 mL, 5.0 eq.), sodium iodide (288 mog,5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7ene (DBU, 0.17 mL, 3.0 eq.)were added. The reaction was shaken at room temperature for 12-16 hours.The reaction mixture was poured into a polypropylene syringe barrelfitted with a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide.

N-Hydroxy-2-(4-methoxy-benzenesulfanyl)-propionamide resin prepared inStep B (175 mg, 1.1 meq/g) was suspended in DCM (3.0 mnL) and 70%tert-butylhydroperoxide (1.0 mL) and benzenesulfonic acid (50 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2), MEOH (2×2mL), and DCM (2×2 mL). The resin wasdriedin vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

N-Hydroxy-2-(4-methoxy-benzenesulfanyl)-propionamide resin prepared inStep B (175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and mCPBA (180mg) was added. The reaction mixture was shaken on an orbital shaker atroom temperature for 12-24 hours. The reaction was filtered and washedwith DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step E: Cleavage of N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-propionamidefrom resin.

The N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-propionamide resin preparedin Step D (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0mnL) was added. The reaction was shaken for 1 hour at room temperature.The reaction was filtered and the resin washed with DCM (2×1 mL). Thefiltrate and the washing were combined and concentrated to dryness on aSavant SpeedVac Plus. Methanol (1 mL) was added and the mixtureconcentrated.

84% @ 215 nm; ¹H NMR (DMSO-d-6) δ 10.75 (brs, 1 H), 7.95 (brs, 1 H),7.71 (dd, 2 H), 7.16 (dd, 2 H), 3.87 (s, 3 H), 3.83 (q, 1 H), 1.26 (d, 3H).

The hydroxamic acids of Examples 111-113 are synthesized usingappropriate starting materials and following the steps in example 110.

EXAMPLE 111

N-Hydroxy-2-(4-methoxy-benzenesulfanyl)-propionamide. 72% @ 215 nm

N-Hydroxy-2-(4-methoxy-benzenesulfmyl)-propionamide. 76% @ 215 nm; ¹HNMR (DMSO d-6) δ 10.90 & 10.60 (brs, 1 H), 7.95 (brs, 1 H) 7.61 & 7.52(dd, 2 H), 7.15 & 7.10 (dd, 2 H), 3.83 & 3.82 (s, 3 H), 3.42 & 3.28 (q1H), 1.23 & 0.97 (d, 3H).

EXAMPLE 112

N-Hydroxy-2-(3-methyl-butane-1-sulfanyl)-propionamide. 74% @ 215 nm.

N-Hydroxy-2-(3-methyl-butane-1-sulfanyl)-propionamide. ¹H NMR (DMSO d-6)δ 10.8 (brs 1 H), 7.95 (brs, 1 H), 3.45 & 3.31 (q, 1 H), 2.71 -2.50 (m,2 H), 1.71-1.46 (m, 3 H), 1.33 & 1.25 (d, 3 H), 0.94-0.82 (m, 6 H)

EXAMPLE 113

N-Hydroxy-2-(3-methyl-butane-1-sulfonyl)-propionamide. 84% @ 215 nm.

EXAMPLE 114

N-hydroxy-3-methyl-2-(naphthalen-2-ylsulfanyl)-butyramide

Step A: Coupling of 2-bromo-3-methyl-butyric acid to hydroxylamineresin.

4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin¹(5 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspendedin DMF (40 mL). 2-Bromo-3-methyl-butyric acid (9.96 g, 10.0 eq.) and DIC(9.04 mL, 10.5 eq.) were added. The reaction was shaken on an orbitalshaker at room temperature for 2-16 hours. The reaction was filtered andwashed with DMF (3×20 mL). A sample of resin was removed and subjectedto the Kaiser test. If the test showed the presence of free amine (resinturned blue) the coupling described above was repeated, otherwise theresin was washed with DCM (3×20 mL), MeOH (2×20 mL), and DCM (2×20 mL).The resin was dried in vacuo at room temperature.

Step B: Displacement of bromide with 2-naphthalenethiol.

The 2-bromo hydroxymate resin prepared in Step A (0.15 g, 1.1 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL).2-Naphthalenethiol (138 mg, 5.0 eq.), sodium iodide (129 mg, 5.0 eq.)and 1,8diazabicyclo(5.4.0]undec-7-ene (DBU, 0.078 mL, 3.0 eq.) 5 wereadded. The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacua at room temperature.

Step C: Oxidation of sulfide to sulfoxide.

2-(2-Naphthalenesulfanyl)-N-hydroxypropionamide resin prepared in Step B(175 mg, 1.1 meqig) was suspended in DCM (3.0 mL) and 70%tert-butylhydroperoxide (1.0 mL) benzenesulfonic acid (50 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

2-(2-Naphthalenesulfanyl)-N-hydroxypropionamide resin prepared in Step B(175 mg, 1.1 meqlg) was suspended in DCM (3.0 mL) and mCPBA (180 mg) wasadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step E: Cleavage ofN-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfanyl)-butyramide from resin.

The 2-(2-Naphthalenesulfanyl)-N-hydroxypropionamide resin; prepared inStep B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL)was added. The reaction was shaken for 1 hour at room temperature. Thereaction was filtered and the resin washed with DCM (2×1 mL). Thefiltrate and the washing were combined and concentrated to dryness on aSavant SpeedVac Plus. Methanol (1 mL) was added and the mixtureconcentrated.

83% @ 215 nm; LCMS (API-electrospray) m/z 276 (M+H)¹; ¹H NMR (DMSO d-6)δ 10.7 (brs, 1 H), 7.91 (brs, 1 H), 7.91-7.81 (m, 4 H), 7.55-7.45 (m, 3H), 3.41 (d, 1 H), 2.09-1.97 (m, 1 H), 1.05 (d, 3 H), 0.97 (d, 3 H).

The hydroxamic acids of Examples 115-118 are synthesized usingappropriate starting materials and following the steps in example 114:

EXAMPLE 115

N-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfanyl)butyramide. 67% @ 215 nm.

EXAMPLE 116

N-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfonyl)-butyramide. 97% @ 215 nm;LCMS (API-electrospray) m/z 308 (M+H)⁺.

EXAMPLE 117

N-Hydroxy-3-methyl-2-phenethylsulfanyl-butyramide. 93% @ 215 nm; LCMS(API-electrospray) m/z 254 (M+H)⁺.

EXAMPLE 118

N-Hydroxy-3-methyl-2-phenethylsulfonyl-butyramide. 97% @ 215 nm; LCMS(API-electrospray) m/z 286 (M+H)⁺.

EXAMPLE 119

(1-Hydroxycarbamoyl-propane-1-sulfanyl)-acetic acid methyl ester

Step A: Coupling of 2-bromobutyric acid to hydroxylamine resin.

4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin¹(5 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspendedin DMF (40 mL). 2-Bromobutyric acid (3.0 g, 3.0 eq.) HOBt (4.86 g, 6.0eq.) and DIC (3.75 mL, 4.0 eq.) were added. The reaction was shaken onan orbital shaker at room temperature for 2-16 hours. The reaction wasfiltered and washed with DMF (3×20 mL). A sample of resin was removedand subjected to the Kaiser test. If the test showed the presence offree amine (resin turned blue) the coupling described above wasrepeated, otherwise the resin was washed with DCM (3×20 mL), MEOH (2×20mL), and DCM (2×20 mL). The resin was dried in vacuo at roomtemperature.

Step B: Displacement of bromide with methyl thioglycolate.

The 2-bromo hydroxymate resin prepared in Step A (0.45 g, 1.1 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL). Methylthioglycolate (286 mg, 5.0 eq.), sodium iodide (404 mg, 5.0 eq.) and1,8-diazabicyclo(5.4.0]undec-7-ene (DBU, 0.24 mL, 3.0 eq.) were added.The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide.

(1-Hydroxycarbamoyl-propane-1-sulfanyl)-acetic acid methyl ester resinprepared in Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and70% tert-butylhydroperoxide (1.0 mL) benzenesulfonic acid (50 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

(1-Hydroxycarbamoyl-propane-1-sulfanyl)-acetic acid methyl ester resinprepared in Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) andmCPBA (180 mg) was added. The reaction mixture was shaken on an orbitalshaker at room temperature for 12-24 hours. The reaction was filteredand washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2mL). The resin was dried in vacuo at room temperature.

Step E: Cleavage of (1-Hydroxycarbamoyl-propane-1-sulfanyl)-acetic acidmethyl ester from resin

The (1-Hydroxycarbamoyl-propane-1-sulfanyl)-acetic acid methyl esterresin prepared in Step B (150 mg, 1.2 meq/g) was suspended in DCM (1.0mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour atroom temperature. The reaction was filtered and the resin washed withDCM (2×1 mL). The filtrate and the washing were combined andconcentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) wasadded and the mixture concentrated. LCMS (API-electrospray) m/z 228(M+Na)⁺.

The hydroxamic acids of Examples 120-124 are synthesized usingappropriate starting materials and following the steps in example 119.

EXAMPLE 120

(1-Hydroxycarbamoyl-propane-1-sulfonyl)-acetic acid hydroxyamide. LCMS(API-electrospray) m/z 224 (M+H)⁺.

EXAMPLE 121

(1-Hydroxycarbamoyl-propane-1-sulfinyl)-acetic acid hydroxy amide. 100%@ 220 nm; LCMS (API-electrospray) m/z 240 (M+H)⁺.

EXAMPLE 122

(1-Hydroxycarbamoyl-propane-1 -sulfanyl)-propionic acid hydroxyamide.

¹H NMR (DMSO d-6) δ 10.7 (brs, 1 H), 4.03 (t, 2 H), 2.95 (q, 1 H),2.75-2.70 (m, 1 H), 2.60-2.54 (m, 1 H), 1.741.66 (m, 2 H), 1.58-1.50 (m,4 H), 1.32 (sextet, 2 H), 0.88 (t, 3 H), 0.85 (t, 3 H); LCMS(API-electrospray) m/z 264 (M+H)⁺.

EXAMPLE 123

(1-Hydroxycarbamoyl-propane-1-sulfinyl)-propionic acid hydroxyamide. 83%@ 220 nm; LCMS (API-electrospray) m/z 280 (M+H)⁺.

EXAMPLE 124

(1-Hydroxycarbamoyl-propane-1-sulfonyl)-propionic acid hydroxyamide.100% @ 220 nm;

EXAMPLE 125

2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide

Step A: Coupling of 2-bromo-3-phenyl-propionic acid to hydroxylamineresin.

4-O-Mediylhydroxylamine-phenoxymethylcopoly(styrene-l%-divinylbenzene)-resin¹(5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspendedin DMF (40 mL). 2-Bromo-3-phenyl-propionic acid (3.5 g, 3.0 eq.) HOBt(4.4 g, 6.0 eq.) and DIC (3.4 mL, 4.0 eq.) were added. The reaction wasshaken on an orbital shaker at room temperature for 2-16 hours. Thereaction was filtered and washed with DMF (3×20 mL). A sample of resinwas removed and subjected to the Kaiser tesL If the test showed thepresence of free amine (resin turned blue) the coupling described abovewas repeated, otherwise the resin was washed with DCM (3×20 mL), MeOH(2×20 mL), and DCM (2×20 mL). The resin was dried in vacuo at roomtemperature.

Step B: Displacement of bromide with 4-hydroxythiophenol.

The 2-bromo hydroxymate resin prepared in Step A (0.33 g, 1.2 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL).4-Hydroxythiophenol (250 mg, 5.0 eq.), sodium iodide (297 mg, 5.0 eq.)and 1,8diazabicyclo[5.4.0]undec-7-ene (DBU, 0.18 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DME (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide.

2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide resinprepared in Step B (110 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and70% tert-butylhydroperoxide (0.73 mL) benzenesulfonic acid (36 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 ml), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide resinprepared in Step B (110 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and3nCPBA (132 mg) was added. The reaction mixture was shaken on an orbitalshaker at room temperature for 12-24 hours. The reaction was filteredand washed with DCM (2×2 mL), DME (2×2 mL), MeOH (2×2 mL), and DCM (2×2mL). The resin was dried in vacuo at room temperature.

Step E: Cleavaage of2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide from resin.

The 2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide resinprepared in Step B (110 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) andTFA (1.0 mL) was added. The reaction was shaken for 1 hour at roomtemperature. The reaction was filtered and the resin washed with DCM(2×1 mL). The filtrate and the washing were combined and concentrated todryness on a Savant SpeedVac Plus. Methanol (1 ) was added and themixture concentrated. 84% @ 215 nm; ¹H NMR (OMSO d-6) δ 10.41 (brs, 1H), 7.95 (brs (1 H), 7.30-7.15 (m, 5 H), 7.10 (dd, 2 H), 6.75 (dd, 2 H),3.53 (q, 1 H), 3.05 (dd, 1 H), 2.79 (dd, 1 H).

The hydroxamic acids of Examples 126-130 are synthesized usingappropriate starting materials and following the steps in example 125.

EXAMPLE 126

2-(4-Hydroxybenzenesulfinyl)-N-hydroxy-3-phenyl-propionamide. 73% @ 215nm;

EXAMPLE 127

2-(4Hydroxybenzenesulfonyl)-N-hydroxy-3-phenyl-propionamide. 77% @ 215nm; ¹H NMR (DMSO d-6) δ 10.50 (brs, 1 H), 7.95 (brs, 1 H), 7.68-7.57 (m,2 H), 7.28-7.17 (m, 3 H), 7.08-7.98 (m, 2 H), 6.95-6.87 (m, 2 H), 3.96(t, 1 H), 3.02 (d, 2 H).

EXAMPLE 128

2-(4-Acetylamino-benzenesulfanyl)-N-hydroxy-3-phenyl-propionamide. 86% @215 nm; ¹H NMR (DMSO d-6) δ 10.50 (brs, 1 H), 10.03 (brs, 1 H), 8.13(brs, 1 H), 7.56-7.12 (m, 9 H), 3.67 (q, 1 H), 3.08 (dd, 1 H), 2.84 (dd,1 H), 2.04 (s,3 H)

EXAMPLE 129

2-(4-Acetylamino-benzenesufanyl)-N-hydroxy-3-phenyl-propionarnide.173% @215 nm.

EXAMPLE 130

2-(4-Acetylamino-benzenesulfonyl)-N-hydroxy-3-phenyl-propionamide. 95% @215 nm;

EXAMPLE 131

4-Hydroxycarbamoyl-4-(4-methanesulfanyl-phenylsulfanyl)-butyric acidmethyl ester

Step A: Coupling of 2-bromo-5-methyl glutaric acid to hydroxylamineresin.

4-O-Methylhydroxylanie-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin¹(4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel andsuspended in DMF (40 mL). S-2-Bromo-5-methyl glutarate (3.87 g, 3.0 eq.)HOBt (4.4 g, 6.0 eq.) and DIC (3.4 mL, 4.0 eq.) were added. The reactionwas shaken on an orbital shaker at room temperature for 2-16 hours. Thereaction was filtered and washed with DMF (3×20 mL). A sample of resinwas removed and subjected to the Kaiser test. If the test showed thepresence of free amine (resin turned blue) the coupling descnbed abovewas repeated, otherwise the resin was washed with DCM (3×20 mL), MeOH(2×20 mL), and DCM (2×20 mL). The resin was dried in vacuo at roomtemperature.

Step B: Displacement of bromide with 4-hydroxythiophenol.

The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL).4(Methylthio)thiophenol (206 mg, 5.0 eq.), sodium iodide (197 mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide.

4-Hydroxycarbamoyl-4-(4-methanesulfanyl-phenylsulfanyl)-butyric acidmethyl ester resin prepared in Step B (73 mg, 1.1 meq/g) was suspendedin DCM (1.5 mL) and 70% tert-butylhydroperoxide (0.49 mL)benzenesulfonic acid (24 mg) were added. The reaction mixture was shakenon an orbital shaker at room temperature for 12-24 hours. The reactionwas filtered and washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL),and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

4-Hydroxycarbamoyl-4-(4-methanesulfanyl-phenylsulfanyl)-butync acidmethyl ester resin prepared in Step B (73 mg, 1.1 meq/g) was suspendedin DCM (1.5 mL) and mCPBA (87 mg) was added. The reaction mixture wasshaken on an orbital shaker at room temperture for 12-24 hours. Thereaction was filtered and washed with DCM (2×2 mL), DMF (2×2 mL), MeOH(2×2 mL), and DCM (2×2 mL). The resin was dried in vacua at roomtemperature.

Step E: Cleavage of4-Hydroxycarbamoyl-4-(4-methanesulfanyl-phenylsulfanyl)-butyric acidmethyl ester from resin.

The 4-Hydroxycarbamoyl-4-(4-methanesulfanyl-phenylsulfanyl)-butyric acidmethyl ester resin prepared in Step B (73 mg, 1.2 meq/g) was suspendedin DCM (1.0 mL) and TFA (1.0 naL) was added. The reaction was shaken for1 hour at room temperature. The reaction was filtered and the resinwashed with DCM (2×1 mL). The filtrate and the washing were combined andconcentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) wasadded and the mixture concentrated. 77% @ 215 nm; LCMS(API-electrospray) m/z 316 (M+H)⁺.

The hydroxamic acids of Examples 132-139 are synthesized usingappropriate starting materials and following the steps in example 131.

EXAMPLE 132

4-Hydroxycarbamoyl-4-(4-methanesulfinyl-phenylsulfinyl)-butyric acidhydroxyamide. 79% @ 215 nm; LCMS (API-electrospray) m/z 348 (M+H)⁺.

EXAMPLE 133

4-Hydroxycarbamoyl-4-(4-methanesulfonyl-phenylsulfonyl)-utyric acidhydroxyamide. 78% @ 215 nm; LCMS (API-electrospray) m/z 380 (M+H)⁺.

EXAMPLE 134

4-Hydroxycarbamoyl-4-(4-bromo-benzenesulfanyl)-buyric acid hydroxyamide.93% @ 215 nm.

EXAMPLE 135

4-Hydroxycarbamoyl-4-(4-bromo-benzenesulfinyl)-butyric acidhydfoxyamide. 80% @ 215 nm.

EXAMPLE 136

4-Hydroxycarbamoyl-4-(4-bromo-benzenesulfonyl)-butyric acidhydroxyamide. 77% @ 215 nm.

EXAMPLE 137

4-Hydroxycarbamoyl-4-(2-trifluoromethyl-benzenesulfanyl)-butyic acidhydroxyamide. 93% @ 215 nm.

EXAMPLE 138

4-Hydroxycarbamoyl-4-(2-triuoromethyl-benzenesulfmyl)-butyric acidhydroxyamide. 72% @ 215 nm.

EXAMPLE 139

4-Hydroxycarbamoyl-4-(2-trifiuoromethyl-benzenesulfonyl)-butyric acidhydroxyamide. 90% @ 215 nm.

EXAMPLE 140

2-(3-methoxy-benzenesulfanyl)decanoic acid hydroxamide

Step A: Coupling of 2-bromo-decanoic acid to hydroxylarnine resin.

4-O-Methylhydroxylamine-phenoxymethylcopoly(styrene-l%-divylbenzene)-resin¹(4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel andsuspended in DMF (40 mL). 2-Bromo-decanoic acid (4.07 g, 3.0 eq.) HOBt(4.4 g, 6.0 eq.) and DIC (3.4 mL, 4.0 eq.) were added. The reaction wasshaken on an orbital shaker at room temperature for 2-16 hours. Thereaction was filtered and washed with DMF (3×20 mL). A sample of resinwas removed and subjected to the Kaiser test. If the test showed thepresence of free amine (resin turned blue) the coupling described abovewas repeated, otherwise the resin was washed with DCM (3×20 mL), MEOH(2×20 mL), and DCM (2×20 mL). The resin was dried in vacuo at roomtemperature.

Step B: Displacement of bromide with 3-methoxy-benzenethiol.

The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL).3-Methoxy-benzenethiol (185 mg, 5.0 eq.), sodium iodide (197 mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacua at room temperature.

Step C: Oxidation of sulfide to sulfoxide.

2-(3-Methoxy-benzenesulfanyl)decanoic acid hydroxamide resin prepared inStep B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and 70%tert-butylhydroperoxide (0.49 mL) benzenesulfonic acid (24 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

2-(3-Methoxy-benzenesulfanyl)decanoic acid hydroxamide resin prepared inStep B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and mCPBA (87mg) was added. The reaction mixture was shaken on an orbital shaker atroom temperature for 12-24 hours. The reaction was filtered and washedwith DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step E: Cleavage of 2-(3-methoxy-benzenesulfanyl)decanoic acidhydroxamide from resin.

The 2-(3-methoxy-benzenesulfanyl)decanoic acid hydroxamide reseinprepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) andTFA (1.0 mL) was added. The reaction was shaken for 1 hour at roomtemperature. The reaction was filtered and the resin washed with DCM(2×1 mL). The filtrate and the washing were combined and concentrated todryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and themixture concentrated. 89% @ 215 nm.

The hydroxamic acids of Examples 141-145 are synthesized usingappropriate starting materials and following the steps in example 140.

EXAMPLE 141.

2-(3-Methoxy-benzenesulfinyl)decanoic acid hydroxamide. 96% @ 215 nm.

EXAMPLE 142

2-(3-Methoxy-benzenesulfonyl)decanoic acid hydroxamide. 96% @ 215 nm.

EXAMPLE 143

2-(4-methanesulfanyl-benzenesulfanyI)decanoic acid hydroxamide. 85% @215 nm; LCMS (API-electrospray) m/z 342 (M+H)⁺.

EXAMPLE 144

2-(4-methanesulfinyl-benzenesulfinyl)decanoic acid hydroxamide. 86% @215 nm; LCMS (API-electrospray) m/z 374 (M+H)⁺.

EXAMPLE 145

2-(4-methanesulfonyl-benzenesulfonyl)decanoic acid hydroxamide. 92% @215 nm.

EXAMPLE 146

3-benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionamide

Step A: Coupling of 2-bromo-3-benzyloxy propionic acid to hydroxylamineresin.

4-O-Methylhydroxylamine-phenoxymethyl-opoly(styrene-1%-divinylbenzene)-resin¹(4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel andsuspended in DMF (40 mL). S-2-Bromo-3-benzyloxy-propionic acid (4.2 g,3.0 eq.) HOBT (4.4 g, 6.0 eq.) and DIC (3.4 mL, 4.0 eq.) were added. Thereaction was shaken on an orbital shaker at room temperature for 2-16hours. The reaction was filtered and washed with DMF (3×20 mL). A sampleof resin was removed and subjected to the Kaiser test. If the testshowed the presence of free amine (resin turned blue) the coupling,described above was repeated, otherwise the resin was washed with DCM(3×20 mL), MeOH (2×20 mL), and DCM (2×20 mL). The resin was dried invacuo at room temperature.

Step B: Displacement of bromide with 4-(methylthio)thiophenol.

The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL).4(Methylthio)thiophenol (206 mg, 5.0 eq.), sodium iodide (197 mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide.

3-Benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionamideresin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5mL) and 70% tert-butylhydroperoxide (0.49 mL) benzenesulfonic acid (24mg) were added. The reaction mixture was shaken on an orbital shaker atroom temperature for 12-24 hours. The reaction was filtered and washedwith DCM (2×2 mL), DMF (2×1.5 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

3-Benzyloxy-N-hydroxy-2-(4methanesulfanyl-benzenesulfanyl)-propionamideresin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5mL) and mCPBA (87 mg) was added. The reaction mixture was shaken on anorbital shaker at room temperature for 12-24 hours. The reaction wasfiltered and washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), andDCM (2×2 mL). The resin was dried in vacuo at room temperature.

Step E: Cleavage of3-benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionamidefrom resin.

The3-benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionamideresin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0mnL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour atroom temperature. The reaction was filtered and the resin washed withDCM (2×1 mL). The filtrate and the washing were combined andconcentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) wasadded and the mixture concentrated. 76% @ 215 nm; LCMS(API-electrospray) m/z 350 (M+H)⁺.

The hydroxamic acids of Examples 147-151 are synthesized usingappropriate starting materials and following the steps in example 146.

EXAMPLE 147

3-Benzyloxy-N-hydroxy-2-(4-methanesulfinyl-benzenesulfmyl)-propionamide.70% @ 215 ni; LCMS (API-electrospray) m/z 382 (M+H)⁺.

EXAMPLE 148

3-Benzyloxy-N-hydroxy-2-(4-methanesulfonyl-benzenesulfonyl)-propionamide.63% @ 215 nm; LCMS (API-electrospray) m/z 414 (M+H)⁺.

EXAMPLE 149

3-Benzyloxy-N-hydroxy-2-(2-chloro-benzylsulfanyl)-propionamide. 90% @215 nm.

EXAMPLE 150

3-Benzyloxy-N-hydroxy-2-(2-chloro-benzylsulfinyl)-propionamide. 70% @215 nm.

EXAMPLE 151

3-B enzyloxy-N-hydroxy-2-(2chlorobenzylsulfonyl)-propionamide. 72% @ 215nm.

EXAMLE 152

2-(2 -bromo-benzenesulfanyl)-N-hydroxy-3-(3H-bimdazol ayl)-propionamide

Step A: Coupling of 2-bromo-3-(3H-imidazol-4-yl)-propionic acid tohydroxylamine resin.

4-O-Methylhydroxylamine-phenoxymethylcopoly(styrene-1%-divinylbenzene)-resin¹(4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel andsuspended in DMF (40 mL). S-2-Bromo-3-(3H-imidazol-4-yl)-propionic acid(3.55 g, 3.0 eq.) HOBt (4.4 g,, 6.0. eq.) and DIC (3.4 mL, 4.0 eq.) wereadded. The reaction was shaken on an orbital shaker at room temperaturefor 2-16 hours. The reaction was filtered and washed with DMF (3×20 mL).A sample of resin was removed and subjected to the Kaiser test. If thetest showed the presence of free amine (resin turned blue) the couplingdescribed above was repeated, otherwise the resin was washed with DCM(3×20 mL), MeOH (2×20 mL), and DCM (2×20 mL). The resin was dried invacuo at room temperature.

Step B: Displacement of bromide with 2-bromothiophenol.

The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL).2-Bromothiophenol (249 mg, 5.0 eq.), sodium iodide (197 mg, 5.0 eq.) and1,8-diazabicyclo(5.4.0]undec-7-ene (DBU, 0.12 mL, 3.0 eq.) were addedThe reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide.

2-(2-Bromo-benzenesulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamideresin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5mL) and 70% tert-butylhydroperoxide (0.49 mL) benzenesulfonic acid (24mg) were added. The reaction mixture was shaken on an orbital shaker atroom temperature for 12-24 hours. The reaction was filtered and washedwith DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

2-(2-Bromo-benzenesulfanyl)-N-hydroxy-3-(3H-imidazolfyl)-propionamnideresin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5mL) and mCPBA (87 mg) was added. The reaction mixture was shaken on anorbital shaker at room temperature for 12-24 hours. The reaction wasfiltered and washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), andDCM (2×2 mL). The resin was dried in vacuo at room temperature.

Step E: Cleavage of2-(2-bromo-benzenesulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamidefrom resin.

The2-(2-bromo-benzenesulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamideresin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour atroom temperature. The reaction was filtered and the resin washed withDCM (2×1 mL). The filtrate and the washing were combined andconcentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) wasadded and the mixture concentrated. 86% @ 215 nm.

The hydroxamic acids of Examples 153-154 are synthesized usingappropriate starting materials and following the steps in example 152.

EXAMPLE 153

2-(4-bromo-benzenesulfinyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide.69% @ 215 nm

EXAMPLE 154

2-(4-chloro-benzenesulfonyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide.

EXAMPLE 155

2-(3-fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide

Step A: Coupling of 2-bromo-5-guanidino-pentanic acid to hydroxylamineresin.

4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrenee-1%-divinylbenzene)-resin¹(4.5 g, 1.2 meq/q) was placed in a peptide synthesis vessel andsuspended in DMF (40 mL). S-2-Bromo-5-guanidino-pentanic acid (3.85 g,3.0 eq.) HOBt (4.4 g, 6.0 eq.) and DIC (3.4 mL, 4.0 eq.) were added. Thereaction was shaken on an orbital shaker at room temperature for 2-16hours. The reaction was filtered and washed with DUF (3×20 mL). A sampleof resin was removed and subjected to the Kaiser test. If the testshowed the presence of free amine (resin turned blue) the couplingdescribed above was repeated; otherwise the resin was washed with DCM(3×20 mL), MeOH (2×20 mL), and DCM (2×20 mL). The resin was dried invacua at room temperature.

Step B: Displacement of bromide with 3-fluorothiophenol.

The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meqog) wasplaced in a 20 mL scintillation vial and suspended in TBF (2 mL).3-Fluorothiophenol (169 mg, 5.0 eq.), sodium iodide (197 mg, 5.0 eq.)and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide.

2(3-Fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide resinprepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and70% tert-butylhydroperoxide (0.49 mL) benzenesulfonic acid (24 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), eOH (2×2 mL), and DCM (2×2 mL). The resinwas dried m vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

2-(3-Fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide resinprepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) andmCPBA (87 mg) was added. The reaction mixture was shaken on an orbitalshaker at room temperature for 12-24 hours. The reaction was filteredand washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2mL). The resin was dried in vacuo at room temperature.

Step E: Cleavage of 2-(3-fluorophenylsulfanyl)-5-guanidino-pentanoicacid hydroxyamide from resin.

The 2-(3-fluorophenylsulfanyI)-5-guanidino-pentanoic acid hydroxyamideresin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour atroom temperature. The reaction was filtered and the resin washed withDCM (2×1 mL). The filtrate and the washing were combined andconcentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) wasadded and the mixture concentrated. 93% @ 215 nm.

The hydroxarnic acids of Examples 156-159 are synthesized usingappropriate stariing materials and following the steps in example 155:

EXAMPLE 156

2-(3-Fluorophenylsulfinyl)-5-guanidino-pentanoic acid hydroxyamide. 80%@ 220 nm; LCMS (API-electrospray) m/z 317 (M+H)⁺.

EXAMPLE 157

2-(2-Bromosulfanyl)-5-guanidino-pentanoic acid hydroxyamide. 92% @ 220nm; ¹H NMR (DMSO d-6) δ 10.90 (brs, 2 H), 10.41 (brs, 1H), 7.95 (brs, 1H), 7.66-7.14 (m, 5 H), 3.72 (q, 1 H), 3.13 (q, 2 H), 1.90-1.66 (m, 2H), 1.58-1.43 (2 H).

EXAMPLE 158

2-(2-Bromosulfinyl)-5-guanidino-pentanoic acid hydroxyamide. 79% @ 220nm; LCMS (API-electrospray) m/z 379 (M+H)⁺.

EXAMPLE 159

2-(2-Bromosulfonyl)-5-guanidino-pentanoic acid hydroxyamide. ¹H NMR(DMSO d-6) δ 8.03-7.45 (m, 5 H), 4.52 (q, 1 H), 3.16 (q, 2 H), 2.07-1.90(m, 2 H), 1.66-1.59 (2 H).

EXAMPLE 160

2-(2,5-dichlorobenzenesulfanyl)-octanoic acid hydroxyamide

Step A: Coupling of 2-bromo-octanoic acid to hydroxylamine resin.

4-O-Methylhydroxylamine-phenoxymethylcopoly(styrene-1%-divinylbenzene)-resin¹(10.0 g, 1.2 meq/g) was placed in a peptide synthesis vessel andsuspended in DMF (80 mL). 2-Bromo-octanoic acid (8.4 g, 3.0 eq.) HOBt(8.8 g, 6.0 eq.) and DIC (7.2 mL, 4.0 eq.) were added. The reaction wasshaken on an orbital shaker at room temperature for 2-16 hours. Thereaction was filtered and washed with DMF (3×20 mL). A sample of resinwas removed and subjected to the Kaiser test. If the test showed thepresence of free amine (resin turned blue) the coupling described abovewas repeated, otherwise the resin was washed with DCM (3×20 mL), MeOH(2×20 mL), and DCM (2×20 mL). The resin was dried in vacuo at roomtemperature.

Step B: Displacement of bromide with 2,5-dichlorothiophenoi.

The 2-bromo hydroxymate resin prepared in Step A (0.45 g, 1.2 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (6 mL).2,5-Dichlorothiophenol (483 mg, 5.0 eq.), sodium iodide (404 mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.24 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DIMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL).The resin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide.

2-(2,5-Dichlorobenzenesulfanyl)-octanoic acid hydroxyamide resinprepared in Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and70% tert-butylhydroperoxide (1.0 mL) benzenesulfonic acid (50 mg) wereadded. The reaction mixture was shaken on an orbital s shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried n vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

2-(2,5-Dichlorobenzenesulfanyl)-octanoic acid hydroxyamide resinprepared in Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) andmCPBA (180 mg) was added. The reaction mixture was shaken on an orbitalshaker at room temperature for 12-24 hours. The reaction was filteredand washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2mL). The resin was dried in vacuo at room temperature.

Step E: Cleavage of 2-(2,5-dichlorobenzenesulfanyl)-octanoic acidhydroxyamide from resin.

The 2-(2,5-dichlorobenzenesulfanyl)-octanoic acid hydroxyamide resinprepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) andTFA (1.0 mL) was added. The reaction was shaken for 1 hour at roomtemperature. The reaction was filtered and the resin washed with DCM(2×1 mL). The filtrate and the washing were combined and concentrated todryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and themixture concentrated. 92% @ 215 nm; ¹H NMR (DMSO d-6) δ 10.96 (brs, 1H), 9.26 (brs, 1 H), 7.93-7.76 (m, 3 H), 4.07 (q, 1 H), 2.041.85 (m, 1H), 1.78-1.64 (m, 1 H), 1.32-1.09 (m, 8 H), 0.81 (t, 3 H).

The hydroxamic acids of Examples 161-167 are synthesized usingappropriate starting materials and following the steps in example 160.

EXAMPLE 161

2-(2,5-Dichlorobenzenesulfonyl)-octanoic acid hydroxyamide. 96% @ 215nm.

EXAMPLE 162

2-(3-Methoxybenzenesulfanyl)-octanoic acid hydroxyamide 86% @ 220 nm;LCMS (API-electrospray) m/z 298 (M+H)⁺.

EXAMPLE 163

2-(3-Methoxybenzenesulfinyl)-octanoic acid hydroxyamide 96% @ 220 nm.

EXAMPLE 164

2-(3-Methoxybenzenesulfonyl)tanoic acid hydroxyamide 83% @ 220 nm.

EXAMPLE 165

2-(3,4-Dimethoxybenzenesulfanyl)-octanoic acid hydroxyamide 87% @ 215nm; LCMS (API-electrospray) m/z 328 (Mt)⁺.

EXAMPLE 166

2-(3,4-Dimethoxybenzenesulfinyl)-octanoic acid hydroxyamide 90% @ 215nm.

EXAMPLE 167

2-(3,4-Dimethoxybenzenesulfonyl)-octanoic acid hydroxyamide 87% @ 215nm.

The hydroxamic acid compounds of Examples 168-198 are synthesized usingappropriate starting materials and following the steps in example 160.The crude products are dissolved in DMSO:methanol (1:1, 2 mL) andpurified by reverse phase HPLC under the conditions described below:

Column: ODS-A, 20 mm×50 mm, 5 μm particle size (YMC, Inc. Wilmington,N.C.)

Solvent Gradient Time Water Acetonitrile 0.0 95  5 25 min.  5 95 FlowRate: 15 mL/min.

EXAMPLE 168

2-(2-Benzimidazol-2-ylsulfanyl)-octanoic acid hydroxyamide 81% @ 215 nm;LCMS (API-electrospray) m/z 308 (M+H)⁺.

EXAMPLE 169

2-(2-Benzooxazol-2-ylsulfanyl)-octanoic acid hydroxyamide 72% @ 215 nm;LCMS (API-electrospray) m/z 309 (M+H)⁺.

EXAMPLE 170

2-(2-Benzothiazol-2-ylsulfanyl)-octanoic acid hydroxyamide 72% @ 215 nm;LCMS (API-electrospray) m/z 325 (+H)⁺.

EXAMPLE 171

2-(2-Pyridine-2-sulfanyl)-octanoic acid hydroxyamide 76% @ 215 nm; LCMS(API-electrospray) m/z 269 (M+H)⁺.

EXAMPLE 172

2-(4-Phenyl-thiazole-2-sulfanyl)-octanoic acid hydroxyamide 97% @ 215nm; LCMS (API-electrospray) m/z 336 (M+H)⁺.

EXAMPLE 173

2-(2-Pyridin-2-yl-ethylsulfanyl)-octanoic acid hydroxyaride 84% @ 215nm; LCMS (API-electrospray) m/z 297 (M+H)⁺.

EXAMPLE 174

2-(2-Phenyl-5H-tetrazol-5-ylsulfanyl)-octanoic acid hydroxyanide 67% @215 nm; LCMS (API-electrospray) m/z 338 (M+H)⁺.

EXAMPLE 175

2-(2-Pyrazin-2-yl-ethylsulfanyl)-octanoic acid hydroxyamide 98% @ 215nm; LCMS (API-electrospray) m/z 298 (M+H)⁺.

EXAMPLE 176

2-(1-Methyl-1H-tetrazol-5-ylsulfanyl)-octanoic acid hydroxyamide 66% @215 nm; LCMS (API-electrospray) m/z 274 (M+H)⁺.

EXAMPLE 177

2-(2-Benzimidazol-2-ylsulfinyl)-octanoic acid hydroxyamide 81% @ 215 nm.

EXAMPLE 178

2-(2-Pyridine-2-sulfinyl)-octanoic acid hydroxyamide 76% @ 215 nm;.

EXAMPLE 179

2-(4-Phenyl-thiazole-2-sulfinyl)-octanoic acid hydroxyamide 78% @ 215nn.

EXAMPLE 180

2-(2-Pyrazin-2-yl-ethylsulfinyl)-octanoic acid hydroxyamide 96% @ 215nm; LCMS (API-electrospray) m/z 314 (M+H)⁺.

EXAMPLE 181

2-(3-Oxy-1H-benzimidazole-2-sulfonyl)-octanoic acid hydroxyamide 63% @215 nm; LCMS (API-electrospray) m/z 356 (M+H)⁺.

EXAMPLE 182

2-(4-Phenyl-thiazole-2-sulfonyl)-octanoic acid hydroxyamide 70% @ 215nm; LCMS (API-electrospray) m/z 383 (M+H)⁺.

EXAMPLE 183

2-[2-(1-Oxy-pyridin-2-yl)-ethanesulfonyl]cctanoic acid hydroxyamide 77%@ 215 nm; LCMS (API-electrospray) m/z 345 (M+H)⁺.

EXAMPLE 184

3-(1-Hydroxycarbamoyl-heptsulfanyl)-benzoic acid hydroxyamide. 100% @220 nm; LCMS (API-electrospray) m/z 312 (M+H)⁺.

EXAMPLE 185

3-[4(1-Hydroxycarbamoyl-heptyl]sulfanyl)-phenyl]-propionic acidhydroxyamide. 90% @ 220 nm; LCMS (API-electrospray) m/z 340 (M+H)⁺.

EXAMPLE 186

2-(Thiazol-2-ylsulfanyl)-octanoic acid hydroxyamide. 75% @ 215 nm; LCMS(API-electrospray) m/z 275 (M+H)⁺.

EXAMPLE 187

2-(2,5-Dioxo-imidazolidin-4-ylmethylsulfanyl)octanoic acid hydroxyamide.98% @ 215 nm; LCMS (API-electrospray) m/z 304 (M+H)⁺.

EXAMPLE 188

3-(1-Hydroxycarbamoyl-heptylsulfmyl)-benzoicacid hydroxyamide. 84% @ 220nm; LCMS (API-electrospray) m/z 328 (M+H)⁺.

EXAMPLE 189

3-[4-(1-Hydroxycarbamoyl-heptylsulfinyl)-phenyl]-propionic acidhydroxyamide. 78% @ 220 nm; LCMS (API-electrospray) m/z 356 (M+H)⁺.

EXAMPLE 190

2-(Quinoline-8-sulfinyl)-octanoic acid hydroxyamide. 87% @ 220 nm; LCMS(API-electrospray) m/z 335 (M+H)⁺.

EXAMPLE 191

2-(Naphthalen-2-ylcarbamoylmethanesulfimyl)-cmtanoic acid hydroxyamide.83% @ 220 nm; LCMS (API-electrospray) m/z 391 (M+H)⁺.

EXAMPLE 192

3-(1-Hydroxycarbamoyl-heptylsulfonyl)-benzoic acid hydroxyamide. 72% @215 nm.

EXAMPLE 193

3-[4-(1-Hydroxycarbamoyl-heptylsulfonyl)-phenyl]-propionic acidhydroxyamide. 67% @ 215 nm.

EXAMPLE 194

2-(1H-Imidazole-2-sulfonyl)-octanoic acid hydroxyamide. 95% @ 215 nm;LCMS (API-electrospray) m/z 290 (M+H)⁺.

EXAMPLE 195

2-(Thiazol-2-ylsulfonyl)-octanoic acid hydroxyamde. 91% @ 215 nm; LCMS(API-electrospray) m/z 307 (M+H)⁺.

EXAMPLE 196

2-(Quinoline-8-sulfonyl)-octanoic acid hydroxyamde. 94% @ 220 nm; LCMS(API-electrospray) m/z 351 (M+H)⁺.

EXAMPLE 197

2-(Naphthalen-2-ylcarbamoylmethanesulfonyl)-octanoic acid hydroxyamide.79% @ 220 nm; LCMS (API-electrospray ) m/z 407 (M+H)⁺.

EXAMPLE 198

2-(2,5-Dioxo-inidazolidinyl methylsulfonyl)-octanoic acid hydroxyamide.97% @ 215 nm.

EXAMPLE 199

Step A: Displacement of bromide with 4-fluorothiophenol.

The 2-bromo hydroxymate resin prepared in Example 160, Step A (9.4 g,1.2 meq/g) was placed in a peptide synthesis vessel and suspended in TBF(50 mL). 4Fluorothiophenol (6.6 g, 5.0 eq.), sodium iodide (7.7 g, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 4.6 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours, thenfiltered and washed with DMF (2×30 mL), DMF:water 9:1 (2×30 mL), DMF (30mL), MeOH (2×20 mL), and DCM (2×20 mL). The resin was dried in vacuo atroom temperature.

Step B: Coupling of 2-(4-fluorobenzenesulfanyl)octanoic acidhydroxyamnide resin with benzyl alcohol.

2-(4-Fluorobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared inStep A (330 mg, 1.1 meq/g) was suspended in DMF (2.0 mL) and benzylalcohol (731 mg, 15 eq.) and sodium hydride (237 mg, 15 eq.) were added.The reaction was heated to 80° C. for 15 hours while shaking on anorbital shaker. After cooling to room temperature the mixture wasfiltered and washed with DMF (2×2 mL), DMF:water 9:1 (2×3 mL), MeOH (2×2mL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide.

2-(4-Benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide resin preparedin Step B (110 mg, 1.1 meq/g) was suspended in DCM (2.2 mL) and 70%tert-butylhydroperoxide (0.73 mL) benzenesulfonic acid (36 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

2-(4-Benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide resin preparedin Step B (110 mg, 1.1 meq/g) was suspended in DCM (2.2 mL) and mCPBA(132 mg) was added. The reaction mixture was shaken on an orbital shakerat room temperature for 12-24 hours. The reaction was filtered andwashed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL).The resin was dried in vacuo at room temperature.

Step E: Cleavage of 2-(4-benzyloxy-benzenesulfanyl)-octanoic acidhydroxyamide from resin.

The 2-(4-benzyloxy-phenylsulfanyl)octanoic acid hydroxyamide resinprepared in Step B (110 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) andTFA (1.0 mL) was added The reaction was shaken for 1 hour at roomtemperature. The reaction was filtered and the resin washed with DCM(2×1 mL). The filtrate and the washing were combined and concentrated toS dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and themixture concentrated. The crude product was dissolved in DMSO:methanol(1:1, 2 mL) and purified by reverse phase HPLC under the conditionsdescribed below:

Column: ODS-A, 20mm×50 mm, 5 μm particle size (YMC, Inc. Wilmington,N.C.)

Solvent Gradient Time Water Acetonitrile 0.0 95  5 25 min.  5 95 FlowRate: 15 mL/min.

2-(4-Benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide 100% @ 215 nm;LCMS (API-electrospray) m/z 374 (M+H)⁺.

The hydroxamic acid compounds of Examples 200-220 are synthesized usingappropriate starting materials and following the steps in example 199:

EXAMPLE 200

2-(4-Butoxy-benzenesulfanyl)-octanoic acid hydroxyamide 100% @ 215 nm;LCMS (API-electrospray) m/z 374 (M+H)⁺.

EXAMPLE 201

2-[(2-Piperazine-1-yl-ethoxy)-benzenesulfanyl]-octanoic acidhydroxyamide 98% @ 215 nm; LCMS (API-electrospray) m/z 340 (M+H)⁺.

EXAMPLE 202

2-[4-(5-Hydroxy-pentyloxy)-phenylsulfanyl]-octanoic acid hydroxyamide65% @ 215 nm.; LCMS (API-electrospray) mlz 370 (M+H)⁺.

EXAMPLE 203

2-[4-(3-Pyridin-2-yl-propoxy)-benzenesulfanyl]-octanoic acidhydroxyamide 95% @ 215 nm; LCMS (API-electrospray) m/z 403 (M+H)⁺.

EXAMPLE 204

2-(4-Benzyloxy-phenylsulfinyl)octanoic acid hydroxyamide 100% @ 215 nm

EXAMPLE 205

2-(4-Butoxy-benzenesulfinyl)-octanoic acid hydroxyamide 98% @ 215 nm.

EXAMPLE 206

2-[4-(2-Piperazine-1-yl-ethoxy)-benzenesulfmyl]-octanoic acidhydroxyamide 98% @ 215 nm.

EXAMPLE 207

2-[4-(3-Pyridin-2-yl-propoxy)-benzenesulfinyl]-octanoic acidhydroxyamide 99% @ 215 nm.

EXAMPLE 208

2-(4-Benzyloxy-phenylsulfonyl)-octanoic acid hydroxyamide 100% @ 215 nm

EXAMPLE 209

2-(4-Butoxy-benzenesulfonyl)-octanoic acid hydroxyamide100% @ 215 nm.

EXAMPLE 210

2-[4-(2-Piperazine-1-yl-ethoxy)-benzenesulfonyll-octanoic acidhydroxyamide 97% @ 215 nm.

EXAMPLE 211

2-[4-(3-Pyridin-2-yl-propoxy)-benzenesulfonyl]-octanoic acidhydroxyamide 100% @ 215 nm.

EXAMPLE 212

2-[4-(1-Methyl-pyrrolidin-3-yloxy)-benzenesulfanyl]-octanoic acidhydroxyamide 91% @ 215 nm; LCMS (APIelectrospray) m/z 367 (M+H)⁺.

EXAMPLE 213

2-[4-(1-Ethyl-propoxy)-benzenesulfanyl]-octanoic acid hydroxyamide 100%@ 215 nm; LCMS (API-electrospray) m/z 354 (M+)⁺.

EXAMPLE 214

2-[4-(Tetrahydro-pyran-4-yloxy)-benzenesulfanyl]-octanoic acidhydroxyamide 97% @ 215 nm; LCMS (API-electrospray) m/z 368 (M+H)⁺.

EXAMPLE 215

2-[4-(1-Methyl-pyrrolidin-3-yloxy)-benzenesulfmyl]-octanoic acidhydroxyamide 96% @ 215 nm.

EXAMPLE 216

2-[4-(1-Ethyl-propoxy)-benzenesulfmyl]-octanoic acid hydroxyamide 97% @215 nm.

EXAMPLE 217

2-[(Tetrahydro-pyran-4-yloxy)-benzenesulfinyl]-octanoic acidhydroxyamide 97% @ 215 nm.

EXAMPLE 218

2-[4-(1-Methyl-pyrrolidin-3-yloxy)-benzenesulfonyl]-octanoic acidhydroxyamide 96% @ 215 nm.

EXAMPLE 219

2-[4-(1-Ethyl-propoxy)-benzenesulfonyl] octanoic acid hydroxyamide 100%@ 215 nm.

EXAMPLE 220

2-[4-(Tetrahydro-pyranyloxy)-benzenesulfonyl]-octanoic acid hydroxyamide100% @ 215 nm.

EXAMPLE 221

Step A: Displacement of bromide with 4-bromothiophenol.

The 2-bromo-octanoic acid hydroxymate resin prepared in Example 160,Step A (5.0 g, 1.1 meq/g) was placed in a peptide synthesis vessel andsuspended in THF (60 mL). 4 Bromothiophenol (5.2 g, 5.0 eq.), sodiumiodide (4.1 g, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.5mL, 3.0 eq.) were added. The reaction was shaken at room temperature for12-16 hours, then filtered and washed with DMF (2×30 mL), DMF:water 9:1(2×30 mL), DMF (30 mL), MeOH (2×30 mL), and DCM (2×30 mL). The resin wasdried in vacuo at room temperature.

Step B: Oxidation of sulfide to sulfoxide.

2-(4-Bromobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared inStep A (4.4 g, 1.1 meq/g) was suspended in DCM (60 mL) and 70%tert-butylhydroperoxide (30 mL) benzenesulfonic acid (1.5 g) were added.The reaction mixture was shaken on an orbital shaker at room temperaturefor 12-24 hours. The reaction was filtered and washed with DC (2×30 mL),DMF (2×30 mL), MeOH (2×30 mL), and DCM (2×30 mL). The resin was dried invacuo at room temperature.

Step C: Oxidation of sulfide to sulfone.

2-(4-Bromobenzenesulfanyl)-octanoic acid hydroxyamide resins prepared inStep B (4.4 g, 1.1 meq/g) was suspended in DCM (60 mL) and mCPBA (5.2 g)was added. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×30 mL), DMF (2×30 mL), MeOH (2×30 mL), and DC (2×30 mL). Theresin was dried in vacuo at room temperature.

Step D: Coupling of 2-(4-bromobenzenesulfinyl)-octanoic acidhydroxyamide resin with 4-chlorobenzeneboronic acid.

2-(4-Bromobenzenesulfmyl)-octanoic acid hydroxyamide resin prepared inStep B (150 mg, 1.1 meq/g) was suspended in DME (2.0 mL) and nitrogengas bubbled through the suspension for 1-2 minutes.4-Chlorobenzeneboronic acid (51.6 mg, 2 eq.),tetrakis(triphenylphosphine) palladium(0) (19.07 mg, 0.1 eq.) and sodiumcarbonate (2 M solution, 0.825 mL, 10 eq.) were added. The reaction washeated to 80° C. for 8 hours while shaking on an orbital shaker. Aftercooling to room temperature the mixture was filtered and washed with DME(2×2 mL), DMF:water 9:1 (2×3 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step E: Cleavage of 2-(4′-chloro-biphenyl-1-sulfnyl)octanoic acidhydroxyamide from resin.

The 2-(4′-chloro-biphenylsulfnyl)-octanoic acid hydroxyamide resinprepared in Step D (150 mg, 1.1 meq/g) was suspended in DCM (1.0 mL) andTFA (1.0 mL) was added. The reaction was shaken for 1 hour at roomtemperature. The reaction was filtered and the resin washed with DCM(2×1 mL). The filtrate and the washing were combined and concentrated todryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and themire concentrated. The crude product was dissolved in DMSO:methanol(1:1, 2 mL) and purified by reverse phase HPLC under the conditionsdescribed below:

Column: ODS-A, 20mm×50 mm, 5 μm particle size (YMC, Inc. Wilmington,N.C.)

Solvent Gradient Time Water Acetonitrile 0.0 95  5 25 min.  5 95 FlowRate: 15 mL/min.

2-(4′-Chloro-biphenylfsulfmnyl)-octanoic acid hydroxyamide 96% @ 215 nm;LCMS (API-electrospray) m/z 394 (M+H)⁺.

The hydroxamic acid compounds of Exmples 222-224 are synthesized usingappropriate starting materials and following the steps in example 221:

EXAMPLE 222

2-[4-(5-Chloro-thiophen-2-yl)-benzenesulfmnyl]-octanoic acidhydroxyamide 100% @ 215 nm; LCMS (API-electrospray) m/z 400 (M+H)⁺.

EXAMPLE 223

2-(4′-Chloro-biphenylsulfonyl)-octanoic acid hydroxyamide 94% @ 215 nm;LCMS (API-electrospray) m/z 410 (M+H)⁺.

EXAMPLE 224

2-[4-(5-Chloro-thiophen-2-yl)-benzenesulfonyl]ctanoic acid hydroxyamide85% @ 215 nm; LCMS (API-electrospray) m/z 416 (M+H)⁺.

EXAMPLE 225

Step A: Coupling of 2-(4-bromobenzenesulfanyl)-Octanoic acidhydroxyamide resin with N-(3-aminopropyl)-morpholine.

2-(4-Bromobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared inExample 199, Step A (100 mg, 1.1 meq/g) was suspended in dioxane (2.0mL) and nitrogen gas bubbled through the suspension for 1-2 minutes.N-(3-Aminopropyl)-morpholine (346 mg, 20 eq.),tris(dibenzylideneacetone)-dipalladium(0) (22 mg, 0.2 eq.),(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl((S)-BINAP, 60 mg,0.8 eq.) and sodium tert-butoxide (207 mg, 18 eq.) were added. Thereaction was heated to 80° C. for 8 hours while shaking on an orbitalshaker. After cooling to room temperature the mixture was filtered andwashed with DMF (2×2 mL), DME:water 9:1 (2×3 mL), MeOH (2×2 mL), and DCM(2×2 mL). The resin was dried in vacuo at room temperature.

Step B: Cleavage of2-[4-(3-morpholin-4-yl-propylamino)-phenylsulfanyl]-octanoic acidhydroxyamide from resin.

The 2-[4-(3-morpholin-4-yl-propylamino)-phenylsulfanyl]-octanoic acidhydroxyamide resin prepared in Step A (100 mg, 1.1 meq/g) was suspendedin IJM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for1 hour at room temperature. The reaction was filtered and the resinwashed with DCM (2×1 mL). The filtrate and the washing were combined andconcentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) wasadded and the mixture concentrated. The crude product was dissolved inDMSO:methanol (1:1, 2 mL) and purified by reverse phase HPLC under theconditions described below:

Column: ODS-A, 20mm×50 mm, 5 μm particle size (YMC, Inc. Wilmington,N.C.)

Solvent Gradient Time Water Acetonitrile 0.0 95  5 25 min.  5 95 FlowRate: 15 mL/min.

2-[4-(3-morpholin-4-yl-propylamino)-phenylsulfanyl]-octanoic acidhydroxyamide 88% @ 215 nm; LCMS (API-electrospray) m/z 410 (M+H)⁺.

The hydroxamic acid compounds of Examples 226-231 are synthesized usingappropriate stardng materials and following the steps in this example:

EXAMPLE 226

2-[4-(Biphenylylamino)-phenylsulfanyl]-octanoic acid hydroxyamide 95% @215 mm; LCMS (API-electrospray) m/z 435 (M+H)⁺.

EXAMPLE 227

2-[4-(Pyridin-4-ylamino)-phenylsulfanyl]-octanoic acid hydroxyamide 97%@ 215 nm; LCMS (API-electrospray) m/z 360 (M+H)⁺.

EXAMPLE 228

2-(4-Cyclopentylamino-phenylsulfanyl)octanoic acid hydroxyamide 77% @215 nm; LCMS (API-electrospray) m/z 351 (M+H)⁺.

EXAMPLE 229

2-(4-Methylamino-phenylsulfanyl)octanoic acid hydroxyamide 99% @ 215 nm;LCMS (API-electrospray) m/z 297 (M+H)⁺.

EXAMPLE 230

2-(4-Piperidin-1-yl-phenylsulfanyl)-octanoic acid hydroxyamide 72% @ 215nm; LCMS (API-electrospray) m/z 351 (M+H)⁺.

EXAMPLE 231

2-(4-Piperazin-1-yl-phenylsulfanyl)-octanoic acid hydroxyamide 74% @ 215nm; LCMS (API-electrospray) m/z 352 (M+H)⁺.

EXAMPLE 232

Step A: Displacement of bromide with 4hydroxythiophenol.

The 2-bromo-octanoic acid hydroxymate resin prepared in Example 160,Step A (15.0 g, 1.1 meq/g) was placed in a peptide synthesis vessel andsuspended in THF (120 mL). 4-Hydroxythiophenol (11.3 g, 5.0 eq.), sodiumiodide (13.5 g, 5.0 eq.) and 1,8-diazabicyclo(5.4.0]undec-7-ene (DBU,8.1 mL, 3.0 eq.) were added. The reaction was shaken at room temperaturefor 12-16 hours, then filtered and washed with DMF (2×60 mL), DMF:water9:1 (2×60 mL), DMF (60 mL), MeOH (2×60 mL), and DCM (2×60 mL). The resinwas dried in vacuo at room temperature.

Step B:Coupling of 2-(4-hydroxybenzenesulfanyl)-octanoic acidhydroxyamide resin with benzene sulfonyl chloride.

2-(4-Hydroxybenzenesulfanyl)-octanoic acid hydroxyamide resin preparedin Step A (240 mg, 1.2 meq/g) was suspended in DCM (3.0 mL). Benzenesulfonyl chloride (225 mg, 5 eq.), and triethylamine (0.06 mL, 2 eq.)were added. The reaction was shaken on an orbital shaker at roomtemperature for 8 hours, then filtered and washed with DME (2×2 mL),DMF:water 9:1 (2×3 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin wasdried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide.

Benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl esterresin prepared in Step B (80 mg, 1.2 meq/g) was suspended in DCM (3 mL),and 70% tert-butylhydroperoxide (1 mL) benzenesulfonic acid (23 mg)were added. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12 -24 hours. The reaction was filtered and washed withDCM (2×3 mL), DMF (2×3 mL), MeOH (2×3 mL), and DCM (2×3 mL). The resinwas dried in vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

Benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl esterresin prepared in Step B (80 mg, 1.2 meq/g) was suspended in DCM (3 mL)and mCPBA (84 mg) was added. The reaction mixture was shaken on anorbital shaker at room temperature for 12-24 hours. The reaction wasfiltered and washed with DCM (2×3 mL), DNF (2×3 mL), MeOH (2×3 mL), andDCM (2×3 mL). The resin was dried in vacuo at room temperature.

Step E: Cleavage of benzenesulfonic acid4(l-hydroxycarbamoyl-heptylsulfanyl)-phenyl ester resin.

The benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenylester resin prepared in Step B (80 mg, 1.2 meq/g) was suspended in DCM(1.0 mL) and TFA (1.0 mL) was added The reaction was shaken for 1 hourat room temperature. The reaction was filtered and the resin washed withDCM (2×1 mL). The filtrate and the washing were combined andconcentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) wasadded and the mixture concentrated The crude product was dissolved inDMSO:methanol (1:1, 2 mL) and purified by reverse phase HPLC under theconditions described below:

Column: ODS-A, 20 mm×50 mm, 5 μm particle size (YMC, Inc. Wilmington,N.C.)

Solvent Gradient Time Water Acetonitrile 0.0 95  5 25 min.  5 95 FlowRate: 15 mL/min.

Benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl ester91% @ 215 nm; LCMS (API-electrospray) m/z 424 (M+H)⁺.

The hydroxamic acid compounds of Examples 233-240 are synthesized usingappropriate starting materials and following the steps in example 232:

EXAMPLE 233

2,5-Dichloro-thiophene-3-sulfonic acid4-(1-hydroxycarbamoyl-heptylsulfanyl)-hydroxyamide 98% @ 215 mm; LCMS(API-electrospray) m/z 498 (M+H)⁺.

EXAMPLE 234

Ethanesulfonic acid 4(1-hydroxycarbamoyl-heptylsulfanyl)-hydroxyamide.72% @ 215 nm LCMS (API-electrospray) m/z 376 (M+H)⁺.

EXAMPLE 235

5-Chloro-1,3-dimethyl-1H-pyrazolesulfonic acid4-(I-hydroxycarbamoyl-heptylsulfinyl)-hydroxyamide 99% @ 215 nm; LCMS(API-electrospray) m/z 492 (M+H)⁺.

EXAMPLE 236

2,5-Dichloro-thiophene-3-sulfonic acid4(1-hydroxycarbamoyl-heptylsulfinyl)-hydroxyamide 96% @ 215 nm; LCMS(API-electrospray) m/z 514 (M+H)⁺.

EXAMPLE 237

5-Pyridin-2-yl-thiophene-2-sulfonic acid4(1-hydroxycarbamoyl-heptylsulfinyl)-hydroxy amide 96% @ 215 nm; LCMS(API-electrospray) m/z 523 (M+H)⁺.

EXAMPLE 238

2-Nitro-benzenesulfonic acid4-(1-hydroxycarbamoyl-heptylsulfonyl)-hydroxyamide 97% @ 215 nm; LCMS(API-electrospray) m/z 501 (M+H)⁺.

EXAMPLE 239

3-Bromo-2-chloro-thiophene-2-sulfonic acid4-(1-hydroxycarbamoyl-heptylsulfonyl)-hydroxyamide 97% @ 215 nm; LCMS(API-electrospray) m/z 576 (M+H)⁺.

EXAMPLE 240

Benzo[1,2,5]thiadiazole4sulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfonyl)-hydroxyamide 83% @ 215 nm; LCMS(API-electrospray) m/z 514 M+H)⁺.

EXAMPLE 241

1-Benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidinefcarboxylic acidhydroxyamide

To a stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mmol) andanhydrous K₂CO₃ (10 gm, excess) in dry acetone (100 ml), α-bromo ethylacetate (3.3 gm, 20 mmol) was added in a round bottom flask and thereaction mixture was heated at reflux for 8 hours with good stirring. Atthe end, the reaction mixture was allowed to cool and the potassiumsalts were filtered off and the reaction mixture was concentrated. Theresidue was extracted with chloroform and washed with H₂O and 0.5 N NaOHsolution. The organic layer was further washed well with water, driedover MgSO₄, filtered and concentrated. (4-methoxy-phenylsulfanyl)-aceticacetic acid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g(100%); MS; 227 (M+H)⁺

To stirred solution of (4-methoxy-phenylsulfanyl)-acetic acid ethylester (4.4 g, 20 mmol), anhydrous K₂CO₃ (10 gm excess) in dry acetone(100 ml) benzyl bromide (3.5 g, 20 mmol) was added and refluxed for 4hrs. At the end, reaction mixture was filtered, concentrated and theresidue was extracted with chloroform It was washed well with water,dried and concentrated. The crude product obtained was converted to(4-benzyloxy-phenylsulfonyl)-acetic acid ethyl ester by oxidaizing withm-chloro perbenzoic acid as described in the example 83. Low meltingsolid. Yield: 6.6 g, 97%; MS: 335 M+1)

To a stirred solution of bis-(2-chloro-ethyl)-benzyl amine hydrochloride(6.6 g, 24.7 mmol), 18-Crown-6 (500 mg), and anhydrous K₂CO₃ (30 gm,excess) in dry acetone (250 ml), (4-benzyloxy-phenylsulfonyl)-aceticacid ethyl ester (8.01 gm, 24 mmol) was added in a round bottom flaskand the reaction mixture was heated at reflux for 16 hours with goodstirling. At the end, the reaction mixture was allowed to cool and thepotassium salts were filtered off and the reaction mixture wasconcentrated. The residue was extracted with chloroform and washed withH₂O. The organic layer was further washed well with water, dried overMgSO₄, filtered and concentrated. The dark brown reaction mixture waspurified by silica gel coumn chromatography by eluting it with 30%ethylacetate: hexane and the product4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acidethyl ester was isolated as Brown oil. Yield: 6.5 g, 55%; MS: 494 (M+H)

4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acidethyl ester (5.0 g, 10.1 mmol) was dissolved in MeOH/THF (1:1, 200 ml)and stirred at room temperature for 72 hrs. At the end reaction mixturewas concentrated and the product was nuetralised with con. HCl bydissolving it in water (200 ml). After the nuetralization reactionmixture was concentrated to dryness. Ice cold water (100 ml) was addedto the solid and filtered. The product4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidinecarboxylic acid wasdried at 50° C. and taken to next step with out any purification.Colorless solid. MP: 66-68; Yield: 4.3 g,91%; MS: 466 (M+H)

Starting from4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid(4.65 g, 10.0 mmol) and following the procedure outlined in example 83,1.1 g of 4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidinefarboxylicacid hydroxyamide was isolated as a colurless solid. Yield 21%; mp 89 °C.; MS: 481.1 lH NMIR (300 MIz, DMSO-d₆): δ2.27 (m, 3H), 2.76-2.79 (m,2H), 3.43 (m, 4H),4.30 (s, 2H), 7.14-7.17 (d,2H), 7.50-7.73 (m, 5H),9.37 (s,1H), 10.53 (s,1H), 11.18 (s,1H).

EXAMPLE 242

4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid hydroxyamide

from 2-[(2-Hydroxy-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine wasprepared according to the general method outlined in example 83 startingfrom diethanolamine (15.0 g, 150). and4-(2-piperidin-1-yl-ethoxy)-benzyl chloride (5.9 g, 20 mmol). Yield 5.5g, (85%); Brown semi-solid; MS: 323 (M+H)⁺

Bis-(2-cloro-ethyl)-[4(2-piperidin-1-yl-ethoxy)-benzyl]-amine wasprepared according to the general method outlined in example 83 startingfrom 2-[(2-Hydroxy-ethyl)- [4(2-piperidin-1-yl-ethoxy)-benzyl]-amine(3.22 g, 10 mmol). Yield 4.0 g (92%); brown semi-solid; MS: 361.1 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from from 4-(butoxy-benzenesulfonyl) acetic acidethyl ester (6.0 g, 20 =mol) andBis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine (8.6 &,20 mmol). Yield 8.0 g (68%); brown oil; MS: 587.7 (M+H)⁺

4(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid was prepared starting from4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.8 g, 10 mmol) dissolved in TBF:methanol3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked upas outlined in example 83. Yield 4.8 g (86%); Spongy brown solid; mp 98°C.; MS: 559.6 (M+H)⁺

Starting from4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid (5.5 g, 10 mmol) and following the procedure outlined in example83, 2.4 g of4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid hydroxy amidewas isolated as a pale yellow solid. Yield 41%; mp155° C. HCl); MS: 574 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.9 (t, 3H),1.1-1.8 (m, 6H), 1.9 (m, 4H), 2.3 (m, 4H), 2.8 (m, 6H), 3.2-3.6 (m, 8H),4.2 (m, 2H), 6.9 - 7.8 (m, 8H), 9.1 (s, 1H), 10.8 (bs, 1H).

EXAMPLE 243

4(4-Butoxy-benzenesulfonyl)-1-[3-(2-morpholinyl-1-ylthoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide

Bis-(2-hydroxy-ethyl)-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-amine wasprepared according to the general method outlined in example 83 startingfrom diethanolamine (15.0 g, 150). and3-(2-morpholin-1-yl-ethoxy)-benzyl chloride (5.9 g, 20 mmol). Yield 6.2g, (95%); Brown semi-solid; MS: 325 (M+H)⁺

Bis-(2-chloroethyl)-[3-(2-morpholin-1-ylethoxy)-benzyl]-amine wasprepared according to the general method outlined in example 83 startingfrom Bis-(2-Hydroxy-ethyl)- [3-(2-morpholin-1-yl-ethoxy)-benzyl]-amine(3.24 g, 10 mmol). Yield 4.0 g (92%); brown semi-solid; MS: 363.1 (M+H)⁺

4(4-Butoxy-benzenesulfonyl)-1-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from from 4-(butoxy-benzenesulfonyl) acetic acidethyl ester (6.0 g, 20 mmol) andBis-(2-chloro-ethyl)-[3-(2-morpholin-1-ylethoxy)-benzyl]-amine (8.6 g,20 mmol). Yield 8.5 g (72%); brown oil; MS: 589.7 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-1-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid was prepared starting from4-(4-Butoxy-benzenesulfonyl)-l-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.8 g, 10mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resultingreaction mixture was worked up as outlined in example 83. Yield 4.8 g(85%); Spongy brown solid; MS: 561.6 (M+H)⁺

Starting from 4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid (5.6g, 10 mmol) and following the procedure outlined in example 83, 4.02 gof4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid hydroxy amidewas isolated as a pale yellow solid. Yield 62%; mp123° C. (HCl); MS: 576 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.9 (t, 3H),1.4 (m, 2H), 1.8 (t, 2H), 2.34.7 (m, 24H), 7.0-7.8 (m, 8H), 9.1 (s, 1H),10.8 (bs, 1H).

EXAMPLE 244

1-Methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide

1-Methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester was prepared according to the general method outlined in example83 starting from 4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (3g, 10 mmol) and methyl-bis-(2-chloro-ethyl)amine (2.2g, 11.6 mmol).Yield 4.0 g, (98%); low melting brown solid; MS: 384 (M+H)⁺

1-Methyl-4-(4butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid wasprepared starting from1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester (7.6 g, 20 minol) dissolved in methanol (300 ml) and 10 N NaOH (35ml). The resulting reaction mixture was worked up outlined in example83. Yield 6.0 g (84%); white solid; mp 195° C.; MS: 356.4 (M+H)⁺

Starting from 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidinecarboxylicacid (4.0 g, 11.2 mmol) and following the procedure outlined in example83, 3.9 g of1-methyl4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyaride was isolated as a yellow powder. Yield 85%; mp 118° C.; MS:371 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.9 (t, 3H), 1.45 (q, 2H), 1.8(q, 2H), 2.1 (s, 3H), 2.3 (d, J =11.4 Hz, 2H), 2.5-3.7 (m, 8H), 4.1 (t,2H), 7.16 (d, 2H), 7.67 (d, 2H)

EXAMPLE 245

1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide

1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester was prepared according to the general method outlined in example83 starting from 4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (3g, 10 mmol) and ethyl-bis-(2-chloro-ethyl)-amine (2.2 g, 10.6 mmol).Yield 3.5 g, (88%); low melting brown solid; MS: 398 (M+H)⁺

1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid wasprepared starting from1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester (.7.94 g, 20 mmol) dissolved in methanol (300 ml) and 10 N NaOH(35 ml). The resulting reaction mixture was worked up as outlined inexample 83. Yield 6.5 g (88%); white solid; mp 162° C.; MS: 370 (M+H)⁺

Startng from1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (3.7g, 10 mmol) and following the procedure outlined in example 83, 3.2 g of1-ethyl(4-butoxy-benzenesulfonyl)-piperidine-4 -carboxylic acidhydroxyamide was isolated as a yellow powder. Yield 76%; mp 98° C.; MS:385 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.9 (t, 3H), 1.2 (t, 3H), 1.46(q, 2H), 1.9 (q, 2H), 2.3 (d, J=11.4 Hz, 2H), 2.5-3.6 (m, 10H), 4.1 (t,2H), 7.16 (d, 2H), 7.67 (d, 2H)

EXAMPLE 246

1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide

1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester was prepared according to the general method outlined inexample 83 starting from 4-(butoxy-benzenesulfonyl) acetic acid ethylester (3 g, 10 mmol) and n-butyl-bis-(2-chloro-ethyl)-amine (2.0g, 10.1mmol). Yield 3.8 g, (89%); low melting brown solid; MS: 426 (M+H)⁺

1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid wasprepared starting from1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester (8.5 g, 20 mmol) dissolved in methanol (300 ml) and 10 NNaOH (35 mL). The resulting reaction mixture was worked up as outlinedin example 83. Yield 7.5 g (88%); white solid; mp 182° C.; MS: 398(M+H)⁺

Starting from1-n-butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (3.9g, 10 mmol) and following the procedure outlined in example 83, 1.8 g of1-n-butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide was isolated as a yellow powder. Yield 40%; mp 121° C.; MS:413 (M+H)^(+;) ¹H NMR (300 MHz, DMSO-d₆): δ 0.9-1.0 (m, 6H), 1.2-1.8 (m,8H), 2.2-2.8 (m, 8H), 3.03.6 (m, 4H), 4.2 (t, 2H), 7.16 (d, 2H), 7.67(d, 2H), 9.3 (bs,1H), 10.3 (bs,1H), 11.1 (bs,1H).

EXAMPLE 247

[4-(4-Chloro-phenoxy)-phenylsulfanyl]-acetic acid ethyl ester

A mixture of 4-bromo chlorobenzene (1.92 g, 10 mmol),(4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol),sodium hydride (460 mg, 10 mmol) and copper(u) chloride (500 mg) wasrefluxed in anhydrous pyridine (50 ml) for 12 hrs. The reaction mixturewas carefilfly quenched with ice cold water and acidified withconcentrated HCl. The product was extracted with choroform, washed wellwith water; dried and concentrated The product was purified by silicagel column chromatography by eluting with 30% ethyl acetate:hexane.Yield 2.5 g (77%); Colorless low melting solid; MS: 323 (M+H)⁺.Alternatively the title compound may be prepared from4-(4-chloro-phenoxy)-benzenethiol and bromo ethyl acetate as describedin example 83.

EXAMPLE 248

[4-(4-Chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester

[4-(4-Chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester wasprepared according to the general method outlined in example 83 startingfrom [(4-chloro-phenoxy)-phenylsulfanyl]-acetic acid ethyl ester (3.23g,10 mmol) and oxone (10 g). Yield 3.5g (99%); oil; MS: 356EI (M+H)⁺

EXAMPLE 249

4-[4-(4-chloro-phenoxy)-benzenesulfonyl]1-methyl-piperidine-4-carboxylicacid hydroxyamide

4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidinecarboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from[4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester ( 2.0g,5.6mmol) and mechlorethanmine hydrochloride (Aldrich), (1.9 g, 10 mmol).Yield 2g ( 81%); brown oil; MS:438 (M+H)⁺

4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylicacid was prepared starting from4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylicacid ethyl ester (4.3 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml)and 10 N NaOH (100 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 3.5 g (86 %); white solid; mp 185° C.;MS:410(M+H)⁺

Starting from 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylic acid (1.0 g, 2.4 mmol) and followingthe procedure outlined in example 83, 460 mg of4-[4-(4-chloro-phenoxy)benzenesulfonyl]1-methyl-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, a white powder. Yield 41%;mp 52° C.; MS: 426 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.3 (s, 3H),2.2-2.9 (m, 6H), 3.5 (bd, 2H), 7.2-7.9 ( m, 8H), 8.1 (s, 1H), 11.0 (bs,1H).

EXAMPLE 250

4-[4-(4-chloro-phenoxy)-benzenesulfonyl]1-ethyl-piperidine-4-carboxylicacid hydroxyamide

4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from[4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (4 g,11.3 mmol) and ethyl-bis-(2-chloro-ethyl)-amine (2.32 g, 16.9 mmol).Yield 3.36 g (66%); brown oil; MS: 452.0 (M+H)⁺

4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylicacid was prepared starting from4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylicacid ethyl ester (3.02 g, 6.7 mmol) dissolved in THF:methanol (3: 1150ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked upas outlined in example 83. Yield 1.8 g (65%); white solid; mp 184° C.;MS: 423.9 (M+H)⁺

Starting from4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylicacid (1.75 g, 4.14 mmol) and following the procedure outlined in example83,,650 mg of4-[4-(4-chloro-phenoxy)-benzenesulfonyl]1-ethyl-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, a white powder. Yield 33%;mp 158° C.; MS: 438.9 (M+H)³⁰ ; ¹H NMR (300 MHz, DMSO-d₆): δ 1.78 (t,J=7.23 Hz, 3H), 2.23-2.27 (m, 2H), 2.51-2.73 (m, 4H), 3.04 (m, 2H), 3.81(d, J=24 Hz, 2H), 7.16-7.27 (m, 4H), 7.50-7.57 (m, 2H), 7.76 (d, J =7Hz, 2H), 9.34 (s, 1H), 9.85 (s, 1H).

EXAMPLE 251

1-Butyl-4-(4-(4-chloro-phenoxy)-benzenesulfonyl-piperidine-4-carboxylicacid hydroxyamide

1-Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from[4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (6 g,18.3 mmol) and butyl-bis-(2-chloro-ethyl)-amine (5.2 g, 22 mmol). Yield3.3 g (38%); yellow oil; MS: 480 (M+H)⁺

1-Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid was prepared staing from1-butyl-4-[4-(4chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid ethyl ester (3.3 g, 6.9 mmol) dissolved in THF:methanol (3:1 150ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked upas outlined in example 83. Yield 2.08 g (67%); white solid; mp 201° C.;MS: 451.9 (M+H)⁺

Starting from1-butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid (2 g, 4.43 mmnol) and following the procedure outlined in example83, 630 mg of1-butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, a white solid. Yield 31%;mp 212° C.; MS: 466.9 (M+H)+; ¹NMR (300 MHz, DMSO-d₆): δ 0.87 (t, J=7.3Hz, 3H), 1.32 (m, 2H), 1.60 (m, 2H), 2.21 (m, 2H), 2.50 (m, 2H), 2.70(q, 2H), 3.00 (m, 2H), 3.57 (d, 2H), 7.16-7.26 (m, 4H), 7.49-7.56 (m,2H), 7.77 (d, J=9 Hz, 2H), 9.34 (s, 1H), 10.13 (s, 1H).

EXAMPLE 252

1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide

1-Benzyl-[4-(4chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from[4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (6 g,16.9 mmol) arid bis-(2-chloro-ethyl)-benzyl amine (6.44 g, 24 mnmol).Yield 2.21 g (25%); yellow oil; MS: 513.9 (M+H)⁺

1-Benzyl-4-[4-(4chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid was prepared starting from1-benzyl-4-[4-(4chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid ethyl ester (2.11 g, 4.1 mmol) dissolved in TBF:methanol (3:1 150ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked upas outlined in example 83. Yield 1.11 g (56%); white solid; mp 201° C.;MS: 485.9 (M+H)⁺

Starting from1-benzyl-4-[4-(4chloro-phenoxy)-benzenesulfonyl]-piperdine-4-carboxylicacid (1 g, 2.06 mmol) and following the procedure outlined in example83, 430 mg of1-benzyl-4-[(4-chlorophenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, an off white solid. Yield39%; mp 90.4° C.; MS: 500.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ2.18-2.30 (m, 2H), 2.73-2.81 (m, 4H), 3.36 (d, 2H), 4.28 (d, J=4.5 Hz,2H), 7.15-7.25 (m, 4H), 7.43-7.48 (m, 3H), 7.51-7.56 (m, 4H), 7.74 (d,J=9 Hz, 2H), 9.53 (s, 1H), 10.47 (s, 1H).

EXAMPLE 253

[4-(3-methyl-butoxy)-phenylsulfanyl]-acetic acid ethyl ester

To stirred solution of (4-Hydroxy-phenylsulfanyl)-acetic acid ethylester (2.12 g, 10 mmol), K₂CO₃ (anhydrous, 10 g) and 1-bromo-3-methylbutane (3 g, excess) was added in boiling acetone. The reaction mixturewas refluxed for 24 hrs and cooled to room temperature. The reactionmixture was filtered and concentrated. The residue obtained wasextracted with chloroform; washed well with water and concentrated. Thecrude product obtained was taken to next step with out purification.Yield 2.7 g (94%); (M+H)⁺283.

EXAMPLE 254

[4-(3-methyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester

[4-(3-methyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester wasprepared according to the general method outlined in example 83 startingfrom [4-(3-methyl-butoxy)-phenylsulfanyl]-acetic acid ethyl ester (2.8g, 10 mmol) and oxone (10 g). Yield 3.0g ( 99%); oil; MS: 314EI (M+H)⁺

EXAMPLE 255

1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide

1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from [4-(3-methyl-butoxy)-phenylsulfonyl]-aceticacid ethyl ester (6.2 g, 20 mnmol) and bis-(2-chloro-ethyl)-benzyl amine(6.44 g, 24 mmol). Yield 8 g (84%); yellow oil; MS: 474 (M+H)⁺

1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid was prepared starting from1-Benzyl[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicethyl ester (4.7 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 3 g (67%); white solid; mp 182° C.; MS:446 (M+H)⁺

Starting from1-Benzyl-[4-[(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid (2.2 g, 5 mmol) and following the procedure outlined in example 83,1.82 g of1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamnide was isolated as a HCl salt, an off white solid. Yield73%; mp 106 ° C; MS: 498 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.8 (d,6H), 1.5 (m,1H), 1.6-2.0 (m, 6H), 2.73-2.81 (m, 4H), 3.5 (d, 2H), 4.28(d, J=4.5 Hz, 2H), 7.15-7.25 (m, 4H), 7.43-7.48 (m, 3H), 7.51-7.56 (m,4H), 7.74 (d, J=9 Hz, 2H), 9.53 (s, 1H), 10.47 (s, 1H).

EXAMPLE 256

1 -Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide

1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from [4-(3-methyl-butoxy)-phenylsulfonyl]-aceticacid ethyl ester (6.2 g, 20 mmol) and butyl-bis-(2-chloro-ethyl)-amine(5.2 g, 22 =mol). Yield 7 g (79%); yellow oil; MS: 440 (M+H)⁺

1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid was prepared starting from1-Butyl-4-[4(3-methyl-butoxy)-benzenesulfonyl]-piperidine4-carboxylicethyl ester (4.4 g, 10 mmol) dissolved in TBF:methanol (3:1 150 ml) andIO N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 3.2 g (77%); white solid; mp 188° C.; MS:412 (M+H)⁺

Starting from1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidinewcarboxylicacid (2.0 g, 5 mmol) and following the procedure outlined in example 83,1.6 g of1-Butyl-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, an off white solid. Yield69%; mp 201° C.; MS: 464 (M+H)⁺.

EXAMPLE 257

[4-(2-Ethyl-butoxy)-phenylsulfanyl]-acetic acid ethyl ester

To stirred solution of (4Hydroxy-phenylsulfanyl)-acetic acid ethyl ester(2.12 g, 10 mmol), K₂CO₃ (anhydrous, 10 g) and 1-bromo-2-ethyl butane (3g, excess) was added in boiling acetone. The reaction mixture wasrefluxed for 24 hrs and cooled to room temperature. The reaction mixturewas filtered and concentrated. The residue obtained was extracted withchloroform; washed well with water and concentrated. The crude productobtained was taken to next step without purification. Yield 2.8 g.(94%);(M+H)⁺297.

EXAMPLE 258

[4(2-Ethyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester

[4-(2-Ethyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester was preparedaccording to the general method outlined in example 83 starting from[4-(2-ethyI-butoxy)-phenylsulfanyl]-acetic acid ethyl ester (2.96 g, 10mmol) and oxone (10 g). Yield 3.1g ( 99%); oil; MS: 329EI (M+H)⁺

EXAMPLE 259

1-Benzyl4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide

1 -Benzyl4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from [4(2-ethyl-butoxy)-phenylsulfonyl]-aceticacid ethyl ester (6.4 g, 20 mmol) and bis-(2-chloro-ethyl)-benzyl amine(6.44 g, 24 mmol). Yield 8 g (82%); yellow oil; MS: 488 (M+H)⁺

1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid was prepared starting from1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicethyl ester (4.8 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 4 g (87%); Semi solid; MS: 460 (M+H)⁺

Starting from1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid (2.2 g, 5 mmol) and following the procedure outlined in example 83,1.02 g of1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, an off white solid. Yield40%; mp 114° C.; MS: 512 (M+H)⁺.

EXAMPLE 260

4-(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxyamide

4-(4-Butoxy-benzenesulfonyl)-1-(3methoxy-benzyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the ceneral method outlinedin example 83 starting from 4-(4-butoxy-benzenesulfonyl)-acedic acidethyl ester (20 g, 77.5 mmol) andbis-(2-chloro-ethyl)-(3-methoxy-benzyl)-amine (34 g, 116 mmol). Yield9.53 g (25%); brown oil; MS: 490.2 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperdine-4-carboxylicacid was prepared stariing from4-(4methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid ethyl ester (2.61 g, 5.34 mmol) dissolved in THF:methanol (3:1 150ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked upasoutlined in example 83. Yield 1 g (41%); brown solid; mp 175° C.; MS:462.0 (M+H)⁺

Starting from4-(4butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid (900 mg, 1.95 mmol) and following the procedure outlined in example83, 200 mg of4-(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, a brown powder. Yield 20%;mp 137° C.; MS: 477.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ0.96 (t,J=7.11 Hz, 3H), 1.48 (m, 2H), 1.73 (m, 2H), 2.27 (m, 2H), 2.47 (m, 2H),2.78 (m, 2H), 3.35 (m, 2H), 3.77 (s, 2H), 4.08 (t, J=6.3 Hz, 3H), 4.32(s, 2H), 7.03 (t, 2H), 7.15 (m, 3H), 7.36 (t, J=7.8 Hz, 1H), 7.64 (d,J=9 Hz, 2H), 9.36 (s, 1H), 10.22 (s, 1H).

EXAMPLE 261

4-(4-Methoxy-benzenesulfonyl)-1-(thiophen-2-yl-benzyl)-piperidine-4-carboxylicacid hydroxyamide

4-(4-Methoxy-benzenesulfonyl)-1-(4thiophen-2-yl-benzyl)-piperidine-4-carboxylicacid ethyl ester was prepared starting from1-(4-Bromo-benzyl)-4-(4-methoxy-benzensulfonyl)-piperidine-4-carboxylicacid ethyl ester (3 g, 6.05 mmol) and 2-(tributylstannyl)-thiophene (6.8g, 18.14 mmol) in the presence of tetrakis palladium (0) in boilingtolune. Yield 1.58 g (52%); brown solid; mp 130° C.; MS: 500 (M+H)⁺

4-(4-Methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylicacid ethyl ester (1.3 g, 2.61 mmol) dissolved in THF:methanol (3:1 150ml) and 10 N NaOH (20 ml). The resulting reaction rnlxture was worked upas outlined in example 83. Yield 950 mg (77%); brown solid; mp 235° C.;MS: 471.8 (M+H)⁺

Starting from4-(4-methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylicacid (920 mg, 1.95 mmol) and following the procedure outlined in example83, 510 mg of4-(4-methoxy-bernzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, a brown solid. Yield 50%;mp 166° C.; MS: 486.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ2.12-2.21 (m,2H), 2.50 (m, 2H), 2.78 (m, 2H), 3.39 (m, 2H), 3.87 (s, 3H), 4.29 (d,2H), 7.17 (m, 3H), 7.54-7.75 (m, 8H), 9.36 (s, 1H), 10.07 (s, 1H)

EXAMPLE 262

4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylicacid hydroxyamide

4-(4-Methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 261. Starting from1-(4-Bromo-benzyl)4-(4-methoxy-benzensulfonyl)-piperidine-4-carboxylicacid ethyl ester (4.65 g, 9.38 mmol) and 2-(tributylstannyl)-pyridine(12.08 g, 32.8 mmol). Yield 2.79 g (60%); brown oil; MS: 495.1 (M+H)⁺

4-(4-Methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-medtoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylicacid ethyl ester (1.83 g, 3.7 mmol) dissolved in ThF:methanol (3:1 150ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked upas outlined in example 83. Yield 1.38 g (80%); off white solid; mp 217°C.; MS: 466.9 (M+H)⁺

Starting from4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylicacid (1.32 g, 2.83 mmol) and following the procedure outlined in example83, 480 mg of4-4-(methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, a white powder. Yield 33%;mp 214° C.; MS: 482.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 2.30 (m, 2H),2.80 (m, 2H), 3.42 (d, J=12.5 Hz, 2H), 3.75 (m, 2H), 3.88 (s, 3H), 4.36(s, 2H), 7.15 (d, J=8.9 Hz, 2H), 7.59-7.74 (m, 4H), 7.84-7.95 (m, 3H),8.55 (d, J=8.1 Hz, 1H), 8.79 (s, 1H), 9.14 (s, 1H), 10.68 (s, 1H), 11.17(s, 1H)

EXAMPLE 263

1-(3,4-Dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide

4-(4-Butoxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83. Starting from (4-butoxy-benzenesulfonyl)acetic acid ethylester (13.2g 44 mmol) (3,4dichloro-benzyl)-bis-(2-chloro-ethyl)-amine(14.3g, mmol). Yield 14.1g (60%), white solid, MP 86° C.; MS: 527.9(M+H)⁺

1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-Butoxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperidine-4-carboxylicacid ethyl ester (14.0 g, 26.5 mmol) dissolved in THF:Methanol (100: 50ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked upas outlined in example 83. Yield 7.87 (60%); off white solid; mp 239 °C; MS: 501.9 (M+H)⁺

Starting1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid (7.7g, 15.5 mmol) and following the procedure outlined in example83, 4.05g of1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, white solid. Yield 48%; mp256.8° C.; MS: 514.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.94 (t, 3H),1.38-1.48 (q, 2H), 1.68-1.75 (q, 2H), 2.27 (m, 4H),2.72 (m, 2H), 4.10(t, 2h), 4.24 (s, 2H), 7.12-7.15 (d, J=8.9, 2H), 7.51-7.53 (d, J=8.1,1H), 7.63-7.65 (d, J=8.8, 2H), 7.72-7.75 (d, J=9.9, 2H), 7.87 (s, 1H),9.36 (s, 1H), 10.5 (s, 1H), 11.2 (s, 1H)

EXAMPLE 264

[4-(4-Chloro-benzyloxy)benzenesulfonyl]-1-methylpiperidine-4-carboxylicacid hydroxamide

[4-(4Chloro-benzyloxy)-benzenesulfonyl-1-methylpiperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from[4-(4-chloro-benzyloxy)-benzenesulfonyl]-acetic acid ethyl ester(13.79g, 37 mmol) and 4-(4-chloro-benzyloxy)-bis-(2- chloro-ethyl)-amine(8.7g, 45 mmol). Yield 10.9 (65%); brown oil; MS: 451.9 (M+H)⁺

[4-(4-Chloro-benzyloxy)-benzenesulfonyl-1-methylpiperidine-4-carboxylicacid was prepared starting from[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylicacid ethyl ester (10.7 g, 24 mmol) dissolved in THF:Methanol (75: 75 mI)and 10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 4.9 g (50%); off white solid; MS: 426.2(M+H)⁺

Starting from[4-(4-Chloro-benzyloxy)-benzenesulfonyl-1-nethylpiperidine-4-carboxylicacid (4.9 g, 12 mmol) and following the procedure outlined in example83, 1.2g of[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylicacid hydroxamide was isolated as a HCl salt, off white solid. Yield 24%;mp 117.8° C.; MS: 438.9 M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 2.2 (m, 2H),2.49 (m, 4H), 2.5 (s, 3 H), 2.6 (m, 2H), 5.2 (s, 2H), 7.25-7.23 (d,t=8.7, 2H), 7.5 (d, t=2.7, 4H), 7.68-7.71 (d, t=9.6, 2H), 9.33 (s, 1H),10.11 (s, 1H)

EXAMPLE 265

4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylicacid hydroxamide

4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from 4-(4-butoxy-benzenesulfonyl)-acetic aceticacid ethyl ester (10.1 g, 34 mmol) and1-(3-phenoxy-benzyl)-bis-(2-chloro-ethyl)-amine (18 g, 50 mnmol). Yield8.9 (49%); brown oil; MS: 552.1 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylicethyl ester (10.7 g, 24 mmol) dissolved in THF.Methanol (75: 50 ml) and10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 5.0 g (76%); off white solid; MS: 524.3(M+H)⁺

Starting from4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylicacid (5.9 g, 11 mmol) and following the procedure outlined in example83, 0.39g of4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylicacid hydroxamide was isolated as a HCl salt, tan solid. Yield 11%; mp92.5° C.; MS: 539.1 (M+H)⁺; ¹H N (300 MHz, DMSO-d₆): δ 0.93-0.97 (t,J=3.6, 3H), 1.49 (m, 2H), 1.73 (m, 2H), 2.51 (m, 4H), 4.09 (t, 2H), 4.29(bs, 2H), 7.06-7.10 (d, J=12, 2H), 7.13-7.15 (m, 3H), 7.39-7.42 (d, 2H),7.63-7.66 (d, 2H), 9.50 (s, 1H), 9.98 (s, 1H)

EXAMPLE 266

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from[1-(4-chloro-benzyloxy)-benzenesulfonyl]-acedic acid ethyl ester (5.47g,15 mmol) and 1-(4-methyl-benzyl)-bis-(2-chloro-ethyl)-amine (5.23 g, 18mmol). Yield 8.0 (96%); brown oil; MS: 542.0 (M+H)

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylicacid was prepared starting from[4-(4-Chloro-benzyIoxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylicacid ethyl ester (7.9 g, 124 mmol) dissolved in THF:Methanol (50: 50 ml)and 10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 4.6g (61%); off white solid, mp 204° C.;MS: 514.2 (M+H)⁺

Starting from[4-(4-Chlorobenzyloxy)-benzenesulfonyl]-1-(4-methylbenzy])-pipendine-4-carboxylicacid (4.2 g, 8 rnmol) and following the procedure outlined in example83, 1.3 g of

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide was isolated as a HCl salt, yellow solid Yield 29%; mp172 ° C; MS: 528.9 (M+H)⁺; ¹H NMR (300 MH, DMSO-d₆): δ

EXAMPLE 267

4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide

4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting 4-(4-Butoxy-benzenesulfonyl)-acetic acid ethylester (5.47 g, 15 mmol) and1-(4-methyl-benzyl)-bis-(2-chloro-ethyl)-amine (15.3 g, 51 mmol). Yield10.1 (57%); white solid, MP 93° C.; MS: 474.1 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicethyl ester (10.0 g, 22 mmol) dissolved in THF:Methanol (50:50 ml) and10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 7.2 g (72%); off white solid, mp 244° C.;MS: 446.3 (M+H)⁺

Starting from4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyI)-piperidine-4-carboxylicacid (6.6 g, 1.5 mmol) and following the procedure outlined in example83, 2.06g of4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide was isolated as a HCl salt, yellow solid. Yield 28%; mp137° C.; MS: 461.3 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.91-0.964 (t,J=7.3, 3H), 1.41 (m, 2H), 1.70 (m, 4H), 1.79 (t, s, 3H), 2.52 (m, 2H),2.76 (m, 2H), 3.33 (bd, 2H), 4.10 (t, 2H), 4.22 (d, 2H), 7.12-7.14 (d,J=8.7, 2H), 7.25-7.28 (d, J=8.1, 2H), 7.42-7.45 (d, J=7.8, 2H),7.63-7.65 (d, J=8.7, 2H), 10.31 (s, 1H), 10.75 (bs, 1H)

EXAMPLE 268

4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-hydroxamidecarboxylic acid hydroxamide

4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting 4(4-Butoxy-benzenesulfonyl)-acetic acid ethylester (5.29 g, 17.6 mmol) and1-(4-cyano-benzyl)-bis-(2-chloro-ethyl)amine

(6.19 g, 21 mmol). Yield 6.8 g (80%); tan oil; MS: 485.0 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-1-(4-cyanobenzyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-Butoxy-benzenesulfonyl)-1-(4-cyanobenzyl)-piperidine-4-carboxylicethyl ester (10.0 g, 124 mmol) dissolved in THF:Methanol (75: 50 ml) and10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield .7g (11%); off white solid; MS: 456.0(M+H)⁺

Starting from4-(4-Butoxy-benzenesulfonyl)-1-(4-cyanobenzyl)-piperidine-4-carboxylicacid (0.600 g, 1.2 mmol) and following the procedure outlined in example83, .21g of4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylicacid hydroxamide was isolated as a HCl salt, off white solid. Yield 34%;mp 241.6° C.; MS: 472.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 0.915-0964(t, J=7.2, 3H), 1.51 (q, 2H),,1.75 (q, 2H), 2.27 (m, 2H), 2.49 (m, 4H),4.11-4.19 (t, 2H), 4.37 (s, 1H), 7.12-7.15 (d, J=8.7, 2H), 7.63-7.66 (d,J=9, 2H), 7.72-7.74 (d, J=7.8, 2H), 9.36 (s, 1H), 10.23 (s, 1H), 11.16(s, 1H)

EXAMPLE 269

4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylicacid hydroxamide

4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting with 4-(4-Butoxy-benzenesulfonyl)-acetic acidethyl ester (6.0 g, 20.0 mmol) andpyridin-4-ylmethyl-bis-(2-chloro-ethyl)- amine.

(4.89 g, 21 inmol). Yield 4.5 g (48%); Brown oil; MS: 461.0 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylicacid was prepared starting from4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylicacid ethyl ester (3.0 g, 6.5 mmol) dissolved in TBF:Methanol (75: 50 ml)and 10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 1.2 g (42%); off white solid; MS: 433.0(M+H)⁺

Staring from4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylicacid (0.864 mg, 2.0 mmol) and following the procedure as outlined inexample 83, 600 mg of 4(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, off white solid. Yield67%; mp 118° C.; MS: 447.9 (M+H)⁺; ¹H NMR (300 MHZ, DMSO-d₆): dO.94 (t,3H), 1.11 (t, 1H), 1.23 (t, 1H), 1.44 (m, 1H), 1.73 (m, 1H),2.34 (m,2H), 2.78 (m, 2H), 3.10 (m, 2H), 3.38 (m, 2H), 4.08 (t, 2H), 4.42 (br s,2H), 7.13 (d, 2H), 7.64 (d, 2H), 7.94 (d, 2H), 8.82(d, 2H), 11.2 (br s,1H), 11.4 (br s,

References:

1 Rickter, L. S.; Desai, M. C. Tetrahedron Letters, 1997, 38, 321-322.

The subject compounds of the present invention were tested forbiological activity according to the following procedures.

In Vitro Gelainase Assay

The assay is based on the cleavage of the thiopeptide substrate((Ac-Pro-Leu-Gly(2 mercapto-4 methyl-pentanoyl)-Leu-Gly-OEt), BachemBioscience) by the enzyme, gelatinase, releasing the substrate productwhich reacts calorimetrically with DTNB((5,5′-dithio-bis(2-nitro-benzoic acid)). The enzyme activity ismeasured by the rate of the color increase.

The thiopeptide substrate is made up fresh as a 20 mM stock in 100% DMSOand the DTNB is dissolved in 100% DMSO as a 100 mM stock and stored indark at room temperature. Both the substrate and DTNB are dilutedtogether to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mM CaCl₂)before use. The stock of human neutrophil gelatinase B is diluted withassay buffer (50 mnM HEPES pH 7.5, 5 mM CaCl₂, 0.02% Brij) to a finalconcentration of 0.15 mnM.

The assay buffer, enzyme, DTNB/substrate (500 μM final concentration)and vehicle or inhibitor are added to a 96 well plate (total reactionvolume of 200 μl) and the increase in color is monitoredspectrophotometrically for 5 minutes at 405 nm on a plate reader.

The increase in OD₄₀₅ is plotted and the slope of the line is calculatedwhich represents the reaction rate.

The linearity of the reaction rate is confirmed (r²>0.85). The mean(x±sem) of the control rate is calculated and compared for statisticalsignificance (p<0.05) with drug-treated rates using Dunnett's multiplecomparison test Dose-response relationships can be generated usingmultiple doses of drug and IC₅₀ values with 95% CI are estimated usinglinear regression (IPRED, HTB).

References: Weingarten, H and Feder, J., Spectrophotometric assay forvertebrate collagenase, Anal. Biochem. 147,437440 (1985).

In Vitro Collazenase Assay

The assay is based on the cleavage of a peptide substrate((Dnp-Pro-Cha-Gly-Cys(iNe)-His-Ala-Lys(NMa)-NH₂), Peptide International,Inc.) by collag,enase releasing the fluorescent NMa group which isquantitated on the fluorometer. Dnp quenches the NiIa fluorescence inthe intact substrate. The assay is run in HCBC assay buffer (50 ImMHEPES, pH 7.0, 5 mM Ca⁺², 0.02% Brij, 0.5% Cysteine), with humanrecombinant fibroblast collagenase (truncated, mw=18,828, WAR, Radnor).Substrate is dissolved in methanol and stored frozen in 1 mM aliquots.Collagenase is stored frozen in buffer in 25 M aliquots. For the assay,substrate is dissolved in HCBC buffer to a final concentration of 10 μMand collagenase to a final concentration of 5 nM. Compounds aredissolved in methanol, DMSO, or HCBC. The methanol and DMSO are dilutedin HCBC to <1.0%. Compounds are added to the 96 well plate containingenzyme and the reaction is started by the addition of substrate.

The reaction is read (excitation 340 nm, emission 444 nm) for 10 min.and the increase in fluorescence over time is plotted as a linear line.The slope of the line is calculated and represents the reaction rate.

The linearity of the reaction rate is confirmed (r²>0.85). The mean(x±sem) of the control rate is calculated and compared for statisticalsignificance (p<0.05) with drug-treated rates using Dunnett's multiplecomparison test. Dose-response relationships can be generated usingmultiple doses of drug and IC₅₀ values with 95% CI are estimated usinglinear regression (IPRED, HTB).

References: Bickett, D. M. et al., A high throughput fluorogenicsubstrate for interstitial collagenase (MMp-1) and gelatinase (MMP-9),Anal. Biochem. 212,58-64 (1993).

Procedure for Measuring TACE Ambition

Using 96-well black microtiter plates, each well receives a solutioncomposed of 10 μL TACE (Inmunex, final concentration 1 μg/mL), 70 μLTris buffer, pH 7.4 containing 10% glycerol (final concentration 10 mM),and 10 μL of test compound solution in DMSO (final concentration 1 μM,DMSO concentration <1%) and incubated for 10 minutes at roomtemperature. The reaction is initiated by addition of a fluorescentpeptidyl substrate (final concentration 100 μM to each well and thenshaking on a shaker for 5 sec.

The reaction is read (excitation 340 nm, emission 420 nm) for 10 min.and the increase in fluorescence over time is plotted as a linear line.The slope of the line is calculated and represents the reaction rate.

The linearity of the reaction rate is confined (r²>0.85). The mean(xtsem) of the control rate is calculated and compared for statisticalsignificance (p<0.05) with drug-treated rates using Dunnett's multiplecomparison test. Dose-response relationships can be generate usingmultiple doses of drug and IC₅₀ values with 95% CI are estimated usinglinear regression

The results obtained following these standard experimental testprocedures are presented in the following table.

IC 50 (nM or % inhibition at 1 micromolar or 10 micromolar (*)) ExampleMMP 1 MMP 9 MMP 13 TACE  1 NT 559.6 193.3 31.62%   2 NT 10.50%    0% 403 3 NT 308.9 169.4 27.43%   4 371 22.20%  17.10%    21%  5 NT 7.7 4.7  25%  6 267 21.4 15.6 40.43%   7 844 72.9 42.1   33%  8 NT 346 307.9  47%  9 313 107 NT 20.30%  10   8% 128 64 54.75%  11 18.80%  2925 319942 12 100 10.8 11 15.50%  13 239 11 14 626 14 158 23 8 17.18%  15 28517 4 137 16 325 9 24 180 17 238.6 8.9 1.4 41.00%  18 540 18.9 11.5 29.2%19 446 95.8 4.8 33.1% 20 423 14.6 18.7   31% 21 318 13.2 15.3   39% 22219 3.2 2.5   30% 23 593 7.9 4.0 40.6% 24 413 20.9 31.3 47.5 25 262 26.78.0 NT 26 304.6 6.3 3.2 34.6 27 629 106 30.1 NT 28 761 3.1 2.0 30.6% 29297 4.3 3.6   41% 30 397 8.1 5.7 25.2% 31 162 15.2 5.7 688 32 13.7 3.71.0 NT 33 318 53.9 18.4 23.9% 34 519.8 34.7 26.1 28.1% 35 455.8 233.648.2 44.9 36 622 83.8 20.7 826 37   9% 31.6% 14.3% 87 38 48.3%  1.7% 5.8% 55.1% 39 29.4% 35.2% 26.6% 69.4 40 583 197 14 160 41 100 10.8 1115.50%  42 262 50.9 6.2 36.5 43 66.1% 34.7% 55.5% 46.6% 44 47.1% 36.9%39.5% 14.9% 45   49% 48.6% 36.7% 20.4% 46 78.9% 79.12%  84.7%  1.4% 4717.1% 12.9% 7.12%  3.3% 48 99.1% 79.1% 85.4% 51.1% 49 10.1% 23.7% 54.6%NT 50 51.1 58.4 10.6 NT 51 178.1 10.4 13.1 48.14%  52 139.3 7.9 9.1 NT53 647.9 27.80%  188 52.57%  54 110 66 21 55.10%  55 303 10 7 21.70%  56299 16 12   65% 57 258 332 191 16.57%  58 211 35 39 7.70% 59 30.20%  447141 24.86%  60 NT 184 NT 23.60%  61 258 38 22 17.21%  62 522 174 43 66963 156 9 3 203 64 40.90%  25.60%  36.70%  29.70%  65 1000 63 13 42.21% 66 1600 131 226 42.33%  67 364 2.3 43.7 690 68 297 29 27 522 69 574.5120.2 90 41.32%  70 1139 88.80%  127 764 71 1000 63 13 42.21%  72 117 111 51.64%  73 300 141 12 20.17%  74 138.1 9.2 4.3 47.86%  75 672.3 83.432.7 23.77%  76 805 NT 500 NT 77 205.5 NT 170 NT 78 262 560 34 24.58% 79 25 0.54 0.4 805 80 22.1%   26% 63.6% 191  81a 2036 230.9 43.9 27.1 81b 3765 154 15.7 228 82 237.6 19.4 5.1 34.5% 83 492 10.2 2.0 229 84519 8.8 2.0 213 85 450 5.8 1.5 115 86 494 16.8 1.5 222 87 368 5.0 1.6170.7 88 1329 12.8 3.1 610 89 1389 38.6 7.0   49% 90 598 10.3 2.2 71.991 1929 13.3 10.8 503 92 59.6% 649 148 9.7 93 56.3% 452 38 15.8% 94 2640138 28.6 22.9 95 3681 364 33.1 25.4% 96 4437 374 33.8 18.1 97 5109 48443.7 20.20%  98 2383 3.8 1.2 154 99 656 16.2 2.4 250 100  4729 19.1 5.339.5% 101  642 12.3 2.1 197 102  662 33.7 1.9   53% 103  1306 45.1 8.8470 104  2610 3.1 1.4 208 105  1214 44.2 4.1 50.2% 106  3788 5.1 0.9 631107  629 26.8 2.5 293 108  2896 5.4 1.7 270 109  393 2.7 2.5 386 241  48.2%* 2.7 15.8 277 242  1950 2 1.3 581 243  2181 1.9 1.5 506 244  34179.8 1.5 594 245  7062 43.4 2.2 51.95%* 246  50.30%* 28.3 2.4 880 249 1412 2 1.6 270 250  1717 1.6 0.8 413 251  1067 0.8 0.9 301 252  801 1.10.9 278 255  2558 3.6 1.5 565 256  10000 7.2 2.9 43.01%* 259  3160 14.35.3    39%* 260  1495 2.9 1.3 272 261  513 10.9 2.7 273 262  422 6.1 2.3298 263  3669 20.3 5.2 57.70%* 264  4293 2.9 3.1 182 265  1944 9.3 7.81037 266  4746 6 5.7 421 267  3620 5.4 2.3 508 268  2292 2.8 1.1 278269  2071 2.2 1.4 296

Compounds prepared by solid phase synthesis Data: for Examples 110 to240 MMP 13 MMP 13 % % inhibition at inhibition at TACE % Example 0.2 μM0.2 μM inhibition at No MMP 1 MMP 9 (HTS) (manual) 1 mM 110 75 17.6 11110 40.4 112 50 33.7 113  0 13.1 114  0 0 115  0 0 116  0 9.1 117  7 8.1118 24 16.7 119  0 7.8 120 31 19.9 121  0 6.1 122  0 3.1 123  0 2.5 124 0 0 125  5 2.3 126 25 10.4 127 47 29.2 128 1.9 mM 213 nM 91 255 nM19.31 129 90 32.77 130 28 27.9 131 71 20.73 132 71 20.76 133 53 22.04134 25 −9.31 135 79 42.67 136 89 42.69 137 83 13.35 138 20 5.284 139  828.05 140 29 −4.22 141 32 11.76 142 69 54.27 143 53 43.9 144 38 19.7 14545 2.5 146 68 7.317 147 73 11.95 148 15 43.46 149 13 4.408 150 54 1.818151  6 5.927 152  9 10.03 153 12 11.8 154 89 13.14 155 31 −18.62 156 23−2.09 157 19 13.7 158 33 −7.48 159 49 5.852 160 14 −3.57 161  0 12.7 16213 0 163 84 9.515 164 74 62.69 165 71 73.7 166  9 4.16 167 27 8.961 16821 3.688

MMP 13 MMP 13 MMP 13 % % % TACE Ex- inhibition at inhibition atinhibition at % ample 36 nM 0.36 mM 3.6 mM TACE inhibition No. (HTS)(HTS) (HTS) IC₅₀ nM at 1 mM 169 28 40 72 41.7 170 32 49 90 25.5 171 3138 48 16.6 172 34 32 42 29.4 173 18 46 56 25.5 174 10 19 40 27.7 175 1620 37 32.9 176 6 5 16 26.6 177 5 1 9 38.5 178 −10 74 39 26 179 12 32 6042.7 180 14 19 45 34.4 181 6 35 62 15.7 182 −9 −8 7 28.6 183 −6 12 7034.6 184 16 24 44 24.8 185 9 0 23 7.21 186 −14 −4 35 19.5 187 −14 −12 2085.5 188 −27 −24 4 16.2 189 −30 −18 −9 14. 190 −35 −28 −13 38.3 191 −45−3 22 2.9 192 −32 5 61 33.2 193 −32 −15 56 14.9 194 −17 −8 5 5.4 195 −9−2 10 27.0 196 −18 1 11 35.7 197 −33 −26 −3 17.8 198 −39 −7 15 17.1 199−10 −7 30 −1.0 200 37.9 201 50.9 202 10.6 203 32.8 204 7.75 205 84.0 20689.8 207 −6.3 208 67.7 209 31.2 210 52.2 211 20.7 212 56.0 213 −17.5 21411.03 215 895 60.12 216 2.49 217 55.1 218 380 68.7 219 7.3 220 256 53.1221 146 98.9 222 212 89.3 223 226 107.3 224 404 75.0 225 96.6 114.3 22628 22 28 2.2 227 15 −16 −22 7.3 228 37 28 65 6.8 229 29 17 33 34.4 23029 31 26 700 72.1 231 23 13 5 41.6 232 30 17 42 20.8 233 33 29 46 19.8234 26 28 40 18.4 235 59 70 70 48.3 236 44 44 64 35 237 55 65 72 38.2238 22 11 24 930 54.4 239 54 74 83 45.9 240 48 51 46 40.3

Compounds of this invention may be administered neat or with apharmaceutical carrier to a patient need thereof. The pharmaceuticalcarrier may be solid or liquid.

Applicable solid carriers can include one or more substances which mayalso act as flavoring agents, lubricants, solubilizers, suspendingagents, fillers, glidants, compression aids or tablet-disintegratingagents or an encapsulating material. In powders, the carrier is a finelydivided solid which is in admixture with the finely divided activeingredient. In tablets, the active ingredient is mixed with a carrierhaving the necessary compression properties in suitable proportions andcompacted in the shape and size desired. The powders and tabletspreferably contain up to 99% of the active ingredient. Suitable solidcarriers include, for example, calcium phosphate, magnesium stearate,talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, lowmelting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such a solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablesodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) and their derivatives,and oils (e.g., fractionated coconut oil and arachis oil). Forparenteral administration the carrier can also be an oily ester such asethyl oleate and isopropyl myristate. Sterile liquid carriers are usedin sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

The compounds of this invention may be administered rectally in the formof a conventional suppository. For administration by intranasal rorintrabronchial inhalation or insufflation, the compounds of thisinvention may be formulated into an aqueous or partially aqueoussolution, which can then be utilized in the form of an aerosol. Thecompounds of this invention may also be administered transdermallythrough the use of a transdermal patch containing the active compoundand a carrier that is inert to the active compound, is non-toxic to theskin, and allows delivery of the agent for systemic absorption into theblood stream via the skin. The carrier may take any number of forms suchas creams and ointments, pastes, gels, and occlusive devices. The creamsand ointments may be viscous liquid or semi-solid emulsions of eitherthe oil in water or water in oil type. Pastes comprised of absorptivepowders dispersed in petroleum or hydrophilic petroleum containing theactive ingredient may also be suitable. A variety of occlusive devicesmay be used to release the active ingredient into the blood stream suchas a semipermeable membrane covering a reservoir containing the activeingredient with or without a carrier, or a matrix containing the activeingredient Other occlusive devices are known in the literature.

The dosage to be used in the treatment of a specific patient sufferingfrom a disease or condition in which MMPs and TACE are involved must besubjectively determined by the attending physician. The variablesinvolved include the severity of the dysfunction, and the size, age, andresponse pattern of the patient. Treatment will generally be initiatedwith small dosages less than the optimum dose of the compound.Thereafter the dosage is increased until the optimum effect under thecircumstances is reached. Precise dosages for oral, parenteral, nasal,or intrabronchial administration will be determined by the administeringphysician based on experience with the individual subject treated andstandard medical principles.

Preferably the pharmaceutical composition is in unit dosage form, e.g.,as tablets or capsules. In such form, the composition is subdivided inunit dose containing appropriate quantities of the active ingredient;the unit dosage form can be packaged compositions, for example packedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

What is claimed is:
 1. A compound according to formula I

wherein: R¹ is alkyl of 1 to 18 carbon atoms, optionally substitutedwith one or two groups selected independently from R⁵; alkenyl of 3 to18 carbon atoms having 1 to 3 double bonds, optionally substituted withone or two groups selected independently from R⁵; alkynyl of 3 to 18carbon atoms having 1 to 3 triple bonds, optionally substituted with oneor two groups selected independently from R⁵; aryl of 6 to 10 carbonatoms, optionally substituted with one or two groups selectedindependently from R⁵; cycloalkyl of 3 to 8 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;saturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷, optionallysubstituted with one or two groups selected independently from R⁵; orheteroaryl-(CH₂)₀₋₆- wherein the heteroaryl group is 5 to 6 memberedwith one or two heteroatoms selected independently from O, S, and N andmay be optionally substituted with one or two groups selectedindependently from R⁵; A is —S—, —SO— or SO₂—; R² and R³, taken with thecarbon atom to which they are attached, form a 5 to 7 memberedheterocyclic ring containing O, S or N—R⁷ optionally having one or twodouble bonds; R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;phenyl or naphthyl optionally substituted with one or two groupsselected independently from R⁵; C₃ to C₈ cycloalkyl or bicycloalkyloptionally substituted with one or two groups selected independentlyfrom R⁵; saturated or unsaturated 5 to 10 membered mono or bicyclicheterocycle containing one heteroatom selected from O, S or NR⁷,optionally substituted with one or two groups selected independentlyfrom R⁵; R⁵ is H, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alkyl, C₂ toC₁₂ alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy,aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆alkoxyaryl, C₁-C₆ alkoxyheteroaryl, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂alkylene dioxy, aryloxy-C₁-C₆ alkyl amine, C₁-C₁₂ perfluoro alkyl,S(O)_(n)—C₁-C₆ alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; OCOO C₁-C₆alkyl, OCOaryl, OCONR⁶, COOH, COO C₁-C₆ alkyl, COaryl, CONR⁶R⁶, CONHOH,NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl, —NR⁶CONR⁶R⁶, NHSO₂CF₃,SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂-C₁-C₆ alkyl, CONHSO₂aryl,SO₂NHCOaryl, CONHSO₂-C₁-C₆ alkyl, CONHSO₂aryl, NH₂, OH, aryl,heteroaryl, C₃ to C₈ cycloalkyl; or saturated or unsaturated 5 to 10membered mono or bicyclic heterocycle containing one heteroatom selectedfrom O, S or NR⁷, wherein C₁-C₆ alkyl is straight or branched,heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; R⁶ is H, C₁ to C₁₈ alkyl optionally substituted with OH; C₃ toC₆ alkenyl, C₃ to C₆ alkynyl, C₁ to C₆ perfluoro alkyl, S(O)_(n)—C₁-C₆alkyl S(O)n aryl where n is 0, 1 or 2; or COheteroaryl, whereinheteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from 0, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alky,S(O)_(n)-C₁-C₆-alkyl, S(O)_(n)- aryl where n is 0, 1 or 2;COO-C₁-C₆-alkyl, COOaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF₃,SO₂NHheteroaryl, SO₂NHCOaryl, CONHSO-C₁-C₆-alkyl, CONHSO₂aryl, aryl, orheteroaryl, where aryl is phenyl or naphthyl, optionally substituted by1 or 2 groups selected independently from halogen, cyano, amino, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 memberedmono or bicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or N-C₁-C₆ alkyl; alkyl of 1 to 18 carbon atoms,optionally substituted with one or two groups selected independentlyfrom R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to 3 doublebonds, optionally substituted with one or two groups selectedindependently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to3 triple bonds, optionally substituted with one or two groups selectedindependently from R⁵; arylalkyl of 7 to 16 carbon atoms, wherein arylis optionally substituted with one or two groups selected independentlyfrom R⁵; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms andheteroaryl contains 1 or 2 heteroatoms selected from O, S or N and isoptionally substituted with one or two groups selected independentlyfrom R⁵; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl isoptionally substituted with one or two groups selected independentlyfrom R⁵; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, whereinthe cycloalkyl or bicycloalkyl group is optionally substituted with oneor two groups selected independently from R⁵; saturated or unsaturatedmono or bicyclic heterocycle containing one heteroatom selected from O,S or N-C₁-C₆ alkyl, optionally substituted with one or two groupsselected independently from R⁵; or R⁸R⁹N-C₁-C₆-alkoxyaryl-C₁-C₆-alkylwhere R⁸ and R⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹together with the interposed nitrogen forms a 5-7 membered saturatedheterocyclic ring optionally containing an oxygen atom, wherein the arylgroup is phenyl or naphthyl; or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1 wherein: R¹ is alkyl of 1 to18 carbon atoms, optionally substituted with one or two groups selectedindependently from R⁵; alkenyl of 3 to 18 carbon atoms having 1 to 3double bonds, optionally substituted with one or two groups selectedindependently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3triple bonds, optionally substituted with one or two groups selectedindependently from R⁵; aryl of 6 to 10 carbon atoms, optionallysubstituted with one to two groups selected independently from R⁵;cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one totwo groups selected independently from R⁵; saturated or unsaturated monoor bicyclic heterocycle of from 5 to 10 members containing oneheteroatom selected from O, S or NR⁷, optionally substituted with one totwo groups selected independently from R⁵; or heteroaryl-(CH₂)₀₋₆-wherein the heteroaryl group is 5 to 6 membered with one or twoheteroatoms selected independently from O, S, and N and may beoptionally substituted with one or two groups selected independentlyfrom R⁵; A is —S—, —SO— or SO₂—; R² and R³, taken with the carbon atomto which they are attached, form a 5 to 7 membered heterocyclic ringcontaining O, S or N—R⁷ optionally having one or two double bonds; R⁴ ishydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with oneor two groups selected independently from R⁵; alkenyl of 3 to 18 carbonatoms having 1 to 3 double bonds, optionally substituted with one or twogroups selected independently from R⁵; alkynyl of 3 to 18 carbon atomshaving 1 to 3 triple bonds, optionally substituted with one or twogroups selected independently from R⁵; phenyl or naphthyl optionallysubstituted with one or two groups selected independently from R⁵; C₃ toC₈ cycloalkyl or bicycloalkyl optionally substituted with one or twogroups selected independently from R⁵; R⁵ is H, F, Cl, Br, I, CN, CHO,C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂-C₁₂alkynyl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆alkynyloxy, C₁-C₆ alkoxyaryl, C₁-C₆ alkoxyheteroaryl,C₁-C₆-alkylamino-C₁-C₆ alkoxy, C₁-C₂-alkylene dioxy, aryloxy-C₁-C₆ alkylamine, C₁-C₁₂ perfluoro alkyl, S(O)_(n)-C₁-C₆ alkyl, S(O)_(n)-aryl wheren is 0, 1 or 2; OCOO-C₁-C₆ alkyl, OCOOaryl, OCONR⁶, COOH, COO-C₁-C₆alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl,NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl, SO₂NHCOaryl, CONHSO₂-C₁-C₆ alkyl,CONHSO₂aryl, NH₂, OH, aryl, heteroaryl, C₃ to C₈ cycloalkyl; orsaturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷; wherein heteroarylis a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3heteroatoms selected independently from O, S or NR⁷ and aryl is phenylor naphthyl, optionally substituted by 1 or 2 groups selectedindependently from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆alkoxy, or hydroxy; R⁶ is H, C₁ to C₁₈ alkyl optionally substituted withOH; C₃ to C₆ alkenyl, C₃ to C₆ alkynyl, C₁ to C₆ perfluoro alkyl, S(O),alkyl or aryl where n is 0, 1, or 2; or COheteroaryl; wherein heteroarylis a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3heteroatoms selected independently from O, S or NR⁷ and aryl is phenylor naphthyl, optionally substituted by 1 or 2 groups selected fromhalogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; andR⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl,S(O)_(n)-alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; COOalkyl, COOaryl,CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶,SO₂CF₃, SO₂NHheteroaryl, SO₂NHCOaryl,CONHSO₂alkyl, CONHSO₂aryl, aryl, heteroaryl; wherein C₁-C₆ alkyl isstraight or branched, heteroaryl is a 5-10 membered mono or bicyclicheteroaryl group having 1 to 3 heteroatoms selected independently from0, S or NR⁷ and aryl is phenyl or naphthyl, optionally substituted by 1or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl,C₁-C₆ alkoxy, or hydroxy; alkyl of 1 to 18 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds,optionally substituted with one or two groups selected independentlyfrom R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triplebonds, optionally substituted with one or two groups selectedindependently from R⁵; arylalkyl of 7 to 16 carbon atoms, wherein arylis optionally substituted with one or two groups selected independentlyfrom R⁵; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms andheteroaryl contains 1 or 2 heteroatoms selected from O, S or N and isoptionally substituted with one or two groups selected independentlyfrom R⁵; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl isoptionally substituted with one or two groups selected independentlyfrom R⁵; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, whereincycloalkyl or bicycloalkyl is optionally substituted with one or twogroups selected independently from R⁵; saturated or unsaturated mono orbicyclic heterocycle containing one heteroatom selected from O, S orN-C₁-C₆ alkyl, optionally substituted with one or two groups selectedindependently from R⁵; R⁸R⁹N-C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ andR⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹ togetherwith the interposed nitrogen forms a 5-7 membered saturated heterocyclicring optionally containing an oxygen atom, wherein the aryl group isphenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
 3. Acompound according to claim 2 wherein R¹ is phenyl, naphthyl, alkyl of1-18 carbon atoms or heteroaryl such as pyridyl, thienyl, imidazolyl orfuranyl, optionally substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, halogen; orS(O)_(n)-C₁-C₆alkyl C₁-C₆ alkoxyaryl or C₁-C₆ alkoxyheteroaryl; A is—S—, O— or —SO₂—; R² and R³, taken with the carbon atom to which theyare attached, form a 5 to 7 membered heterocyclic ring containing O, Sor N—R⁷ optionally having one or two double bonds; R⁴ is hydrogen, alkylof 1 to 6 carbon atoms, optionally substituted with one or two groupsselected independently from R⁵; alkenyl of 3 to 18 carbon atoms having 1to 3 double bonds, optionally substituted with one or two groupsselected independently from R⁵; alkynl of 3 to 18 carbon atoms having 1to 3 triple bonds, optionally substituted with one or two groupsselected independently from R⁵; phenyl or naphthyl optionallysubstituted with one or two groups selected independently from R⁵; C₃ toC₈ cycloalkyl or bicycloalkyl optionally substituted with one or twogroups selected independently from R⁵; R⁵ is H, C₇-C₁₁ aroyl, C₂-C₆alkanoyl, C₁ to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br,I, CN, CHO, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy,C₃-C₆ alkynyloxy, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂ alkylene dioxy,aryloxy-C₁-C₆ alkyl amine, C₁-C₁₂ perfluoro alkyl,S(O)_(n)-C₁-C₆ alkyl,S(O)_(n)-aryl where n is 0, 1 or 2; OCOO C₁-C₆ alkyl, OCOOaryl, OCONR⁶,COOH, COO C₁-C₆ alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶,NR⁶SO₂aryl, —NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl,SO₂NHCOaryl,CONHSO₂-C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂-C₁-C₆ alkyl,CONHSO₂aryl, NH₂, OH, aryl, heteroaryl, C₃ to C₈ cycloalkyl; saturatedor unsaturated 5 to 10 membered mono or bicyclic heterocycle containingone heteroatom selected from O, S or NR⁷, wherein C₁-C₆ alkyl isstraight or branched, heteroaryl is a 5-10 membered mono or bicyclicheteroaryl group having 1 to 3 heteroatoms selected independently fromO, S or NR⁷ and aryl is phenyl or naphthyl, optionally substituted by 1or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl,C₁-C₆ alkoxy, or hydroxy; R⁶ is H, C₁ to C₁₈ alkyl optionallysubstituted with OH; C₃ to C₆ alkenyl, C₃ to C₆ alknyl, C₁ to C₆perfluoro alkyl, S(O)_(n)alkyl or aryl where n is 0, 1 or 2; orCOheteroaryl; wherein heteroaryl is a 5-10 membered mono or bicyclicheteroaryl group having 1 to 3 heteroatoms selected independently fromO, S or NR⁷ and aryl is phenyl or naphthyl, optionally substituted by 1or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alky,C₁-C₆ alkoxy, or hydroxy; and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂perfluoro alkyl, S(O)_(n)-alkyl, S(O)_(n)-aryl where n is 0, 1 or 2;COOalkyl, COaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶,SO₂CF₃,SO₂iNheteroaryl, SO₂NHCOaryl, CONHSO₂alkyl, CONHSO₂aryl, aryl, orheteroaryl; where aryl is phenyl or naphthyl, optionally substituted by1 or 2 groups selected independently from halogen, cyano, amino, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 memberedmono or bicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or N-C₁-C₆ alkyl; alkyl of 1 to 18 carbon atoms,optionally substituted with one or two groups selected independentlyfrom R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to 3 doublebonds, optionally substituted with one or two groups selectedindependently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to3 triple bonds, optionally substituted with one or two groups selectedindependently from R⁵; arylalkyl of 7 to 16 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroarylcontains 1 or 2 heteroatoms selected from O, S or N and is optionallysubstituted with one or two groups selected independently from R⁵;biphenylalkyl of 13 to 18 carbon atoms, optionally substituted with oneor two groups selected independently from R⁵; arylalkenyl of 8 to 16carbon atoms, optionally substituted with one or two groups selectedindependently from R⁵; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12carbon atoms, optionally substituted with one or two groups selectedindependently from R⁵; saturated or unsaturated mono or bicyclicheterocycle containing one heteroatom selected from O, S or NR-C₁-C₆alkyl, optionally substituted with one or two groups selectedindependently from R⁵; R⁸R⁹N-C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ andR⁹ are independently selected from C₁-C⁶ alkyl or R⁸ and R⁹ togetherwith the interposed nitrogen forms a 5-7 membered saturated heterocyclicring optionally containing an oxygen atom, wherein the aryl group isphenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
 4. Amethod of inhibiting pathological condition or disorder mediated bymatrix metalloproteinases in mammals which comprises administration to amammal in need thereof a therapeutically effective amount of a matrixmetalloproteinase inhibiting compound of the formula

wherein: R¹ is alkyl of 1 to 18 carbon atoms, optionally substitutedwith one or two groups selected independently from R⁵; alkenyl of 3 to18 carbon atoms having 1 to 3 double bonds, optionally substituted withone or two groups selected independently from R⁵; alkynyl of 3 to 18carbon atoms having 1 to 3 triple bonds, optionally substituted with oneor two groups selected independently from R⁵; aryl of 6 to 10 carbonatoms, optionally substituted with one or two groups selectedindependently from R⁵; cycloalkyl of 3 to 8 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;saturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷, optionallysubstituted with one or two groups selected independently from R⁵; orheteroaryl-(CH₂)₀₋₆- wherein the heteroaryl group is 5 to 6membered withone or two heteroatoms selected independently from O, S, and N and maybe optionally substituted with one or two groups selected independentlyfrom R⁵; A is —S—, —SO— or SO₂—; R² and R³, taken with the carbon atomto which they are attached, form a 5 to 7 membered heterocyclic ringcontaining O, S or N—R⁷ optionally having one or two double bonds; R⁴ ishydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with oneor two groups selected independently from R⁵; alkenyl of 3 to 18 carbonatoms having 1 to 3 double bonds, optionally substituted with one or twogroups selected independently from R⁵; alkynyl of 3 to 18 carbon atomshaving 1 to 3 triple bonds, optionally substituted with one or twogroups selected independently from R⁵; phenyl or naphthyl optionallysubstituted with one or two groups selected independently from R⁵; C₃ toC₈ cycloalkyl or bicycloalkyl optionally substituted with one or twogroups selected independently from R⁵; saturated or unsaturated 5 to 10membered mono or bicyclic heterocycle containing one heteroatom selectedfrom O, S or NR⁷, optionally substituted with one or two groups selectedindependently from R⁵; R⁵ is H, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, CI to C₁₂alkyl, C₂ to C₁₂ alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆alkoxy, aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy,C₁-C₆ alkoxyaryl, C₁-C₆ alkoxyheteroaryl, C₁-C₆ alkylamino-C₁-C₆ alkoxy,C₁-C₂ alkylene dioxy, aryloxy-C-C₆ alkyl amine, C₁-C₁₂ perfluoro alkyl,S(O)_(n)-C₁-C₆ alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; OCOO C₁-C₆alkyl, OCOOaryl, OCONR⁶, COOH, COO C₁-C₆ alkyl, COOaryl, CONR⁶R⁶,CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl, -NR⁶CONR⁶R⁶, NHSO₂CF₃,SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂-C₁-C₆ alyl, CONHSO₂aryl,SO₂NHCOaryl, CONHSO₂-C₁-C₆ alkyl, CONHSO₂aryl, NH₂, OH, aryl,heteroaryl, C₃ to C₈ cycloalkyl; or saturated or unsaturated 5 to 10membered mono or bicyclic heterocycle containing one heteroatom selectedfrom O, S or NR⁷, wherein C₁-C₆ alkyl is straight or branched,heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; R⁶ is H, C₁ to C₁₈ alkyl optionally substituted with OH; C₃ toC₆ alkenyl, C₃ to C₆ alkynyl, C₁ to C₆ perfluoro alkyl, S(O)_(n)-C₁-C₆alkyl S(O), aryl where n is 0, 1 or 2;, or COheteroaryl, whereinheteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl,S(O)n-C₁-C₆-alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; COO-C₁-C₆-alkyl,COOaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF₃, SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO-C₁-C₆-alkyl, CONHSO₂aryl, aryl, or heteroaryl, wherearyl is phenyl or naphthyl, optionally substituted by 1 or 2 groupsselected independently from halogen, cyano, amino, nitro, C₁-C₆ alkyl,C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono orbicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or N—C₁-C₆ alkyl; alkyl of 1 to 18 carbon atoms,optionally substituted with one or two groups selected independentlyfrom R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to 3 doublebonds, optionally substituted with one or two groups selectedindependently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to3 triple bonds, optionally substituted with one or two groups selectedindependently from R⁵; arylalkyl of 7 to 16 carbon atoms, wherein arylis optionally substituted with one or two groups selected independentlyfrom R⁵; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms andheteroaryl contains 1 or 2 heteroatoms selected from O, S or N and isoptionally substituted with one or two groups selected independentlyfrom R⁵; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl isoptionally substituted with one or two groups selected independentlyfrom R⁵; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, whereinthe cycloalkyl or bicycloalkyl group is optionally substituted with oneor two groups selected independently from R⁵; saturated or unsaturatedmono or bicyclic heterocycle containing one heteroatom selected from O,S or N—C₁-C₆ alkyl, optionally substituted with one or two groupsselected independently from R⁵; or R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C⁶-alkylwhere R⁸ and R⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹together with the interposed nitrogen forms a 5-7 membered saturatedheterocyclic ring optionally containing an oxygen atom, wherein the arylgroup is phenyl or naphthyl; or a pharmaceutically acceptable saltthereof.
 5. A method according to claim 4 wherein the condition treatedis atherosclerosis, atherosclerotic plaque formation, reduction ofcoronary thrombosis from atheroschlerotic plaque rupture, restenosis,MMP-mediated osteopenias, inflammatory diseases of the central nervoussystem, sking again, angiogenesis, tumor metastasis, tumor growth,osteoarthritis, rheumatoid arthritis, septic arthritis, cornealulceration, abnormal wound healing, bone disease, ptoteinuria,aneurysmal aortic disease, degenerative cartilage loss followingtraumatic joint injury, demyelinating diseases of the nervous system,cirrhosis of the liver, glomerular disease of the kidney, prematurerupture of fetal membranes, inflammatory bowel disease, or periodontaldisease.
 6. A method according to claim 4 wherein the condition treatedis age related macular degeneration, diabetic retinopathy, proliferativevitreoretinopathy, retinopathy of prematurity, ocular inflammation,keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocularangiogenesis/neovascularization and corneal graft rejection.
 7. A methodof treating a pathological condition or disorder mediated by TNF-αconverting enzyme (TACE) in mammals which comprises administration to amammal in need thereof a therapeutically effective amount of a TACEinhibiting compound of the formula

wherein: R¹ is alkyl of 1 to 18 carbon atoms, optionally substitutedwith one or two groups selected independently from R⁵; alkenyl of 3 to18 carbon atoms having 1 to 3 double bonds, optionally substituted withone or two groups selected independently from R⁵; alkynyl of 3 to 18carbon atoms having 1 to 3 triple bonds, optionally substituted with oneor two groups selected independently from R⁵; aryl of 6 to 10 carbonatoms, optionally substituted with one or two groups selectedindependently from R⁵; cycloakyl of 3 to 8 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;saturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷, optionallysubstituted with one or two groups selected independently from R⁵; orheteroaryl-(CH₂)₀₋₆- wherein the heteroaryl group is 5 to 6 memberedwith one or two heteroatoms selected independently from O, S, and N andmay be optionally substituted with one or two groups selectedindependently from R⁵; A is —S—, —SO— or SO₂—; R² and R³, taken with thecarbon atom to which they are attached, form a 5 to 7 memberedheterocyclic ring containing O, S or N—R⁷ optionally having one or twodouble bonds; R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;phenyl or naphthyl optionally substituted with one or two soups selectedindependently from R⁵; C₃ to C₈ cycloalkyl or bicycloalkyl optionallysubstituted with one or two groups selected independently from R⁵;saturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷, optionallysubstituted with one or two groups selected independently from R⁵; R⁵ isH, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alkyl, C₂ to C₁₂ alkenyl,C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy, aryloxy,heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆ alkoxyaryl,C₁-C₆ alkoxyheteroaryl, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂ alkylenedioxy, aryloxy-C₁-C₆ alkyl amine, C₁-C₁₂ perfluoro alkyl, S(O)_(n)-C₁-C₆alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; OCOO C₁-C₆ alkyl, OCOOaryl,OCONR⁶, COOH, COO C₁-C₆ aLkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶,SO₂NR⁶R⁶, NR⁶SO₂aryl, —NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂Nheteroaryl,SO₂NHCOaryl, CONHSO₂-C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl,CONHSO₂-C₁-C₆ alkyl, CONHSO₂aryl, NH₂, OH, aryl, heteroaryl, C₃ to C₈cycloalkyl; or saturated or unsaturated 5 to 10 membered mono orbicyclic heterocycle containing one heteroatom selected from O, S orNR⁷, wherein C₁-C₆ alkyl is straight or branched, heteroaryl is a 5-10membered mono or bicyclic heteroaryl group having 1 to 3 heteroatomsselected independently from O, S or NR⁷ and aryl is phenyl or naphthyl,optionally substituted by 1 or 2 groups selected from halogen, cyano,amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; R⁶ is H, C₁ to C₁₈alkyl optionally substituted with OH; C₃ to C₆ alkenyl, C₃ to C₆alkynyl, C₁ to C₆ perfluoro alkyl, S(O)_(n)-C₁-C₆ alkyl S(O)n aryl wheren is 0, 1 or 2, or COheteroaryl, wherein heteroaryl is a 5-10 memberedmono or bicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or NR⁷ and aryl is phenyl or naphthyl,optionally substituted by 1 or 2 groups selected from halogen, cyano,amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and R⁷ is C₇-C₁₁aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl, S(O)_(n)-C₁-C₆-alkyl,S(O)_(n)-aryl where n is 0, 1 or 2; COO-C₁-C₆-alkyl, COOaryl, CONHR⁶,CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF₃, SO₂NHheteroaryl, SO₂NHCOaryl,CONHSO-C₁-C₆-alkyl, CONHSO₂aryl, aryl, or heteroaryl, where aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedindependently from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclicheteroaryl group having 1 to 3 heteroatoms selected independently fromO, S or N-C₁-C₆ alkyl; alkyl of 1 to 18 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds,optionally substituted with one or two groups selected independentlyfrom R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triplebonds, optionally substituted with one or two groups selectedindependently from R⁵; arylalkyl of 7 to 16 carbon atoms, wherein arylis optionally substituted with one or two groups selected independentlyfrom R⁵; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms andheteroaryl contains 1 or 2 heteroatoms selected from O, S or N and isoptionally substituted with one or two groups selected independentlyfrom R⁵; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl isoptionally substituted with one or two groups selected independentlyfrom R⁵; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, whereinthe cycloalkyl or bicycloalkyl group is optionally substituted with oneor two groups selected independently from R⁵; saturated or unsaturatedmono or bicyclic heterocycle containing one heteroatom selected from O,S or N-C₁-C₆ alkyl, optionally substituted with one or two groupsselected independently from R⁵; or R⁸R⁹N-C₁-C₆-alkoxyaryl-C₁-C₆-alkylwhere R⁸ and R⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹together with the interposed nitrogen forms a 5-7 membered saturatedheterocyclic ring optionally containing an oxygen atom, wherein the arylgroup is phenyl or naphthyl; or a pharmaceutically acceptable saltthereof.
 8. The method according to claim 7 wherein the conditiontreated is rheumatoid arthritis, graft rejection, cachexia, anorexia,inflammation, fever, insulin resistance, septic shock, conjestive heardfailure, inflammatory disease of the central nervous system,inflammatory bowel disease or HIV injection.
 9. A pharmaceuticalcomposition comprising a pharmaceutical carrier and a therapeuticallyeffective amount of a matrix metalloproteinase or TACE inhibitingcompound according to the formula

wherein: R¹ is alkyl of 1 to 18 carbon atoms, optionally substitutedwith one or two groups selected independently from R⁵; alkenyl of 3 to18 carbon atoms having 1 to 3 double bonds, optionally substituted withone or two groups selected independently from R⁵; alkynyl of 3 to 18carbon atoms having 1 to 3 triple bonds, optionally substituted with oneor two groups selected independently from R⁵; aryl of 6 to 10 carbonatoms, optionally substituted with one or two groups selectedindependently from R⁵; cycloalkyl of 3 to 8 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;saturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷, optionallysubstituted with one or two groups selected independently from R⁵; orheteroaryl-(CH₂)₀₋₆- wherein the heteroaryl group is S to 6 memberedwith one or two heteroatoms selected independently from O, S, and N andmay be optionally substituted with one or two groups selectedindependently from R⁵; A is —S—, —SO— or SO₂—; R² and R³, taken with thecarbon atom to which they are attached, form a 5 to 7 memberedheterocyclic ring containing O, S or N—R⁷ optionally having one or twodouble bonds; R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;phenyl or naphthyl optionally substituted with one or two groupsselected independently from R⁵; C₃ to C₈ cycloalkyl or bicycloalkyloptionally substituted with one or two groups selected independentlyfrom R⁵; saturated or unsaturated 5 to 10 membered mono or bicyclicheterocycle containing one heteroatom selected from O, S or NR⁷,optionally substituted with one or two groups selected independentlyfrom R⁵; R⁵ is H, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alkyl, C₂ toC₁₂ alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy,aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆alkoxyaryl, C₁-C₆ alkoxyheteroaryl, C₁-C₆ alkyamino-C₁-C₆ alkoxy, C₁-C₂alkylene dioxy, aryloxy-C₁-C₆ alky amine, C₁-C₁₂ perfluoro alkyl,S(O)_(n)-C₁-C₆ alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; OCOO C₁-C₆alkyl, OCOaryl, OCONR⁶, COOH, COO C₁-C₆ alkyl, COOaryl, CONR⁶R⁶, CONHOH,NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl, -NR⁶CONR⁶R⁶, NHSO₂CF₃,SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂-C₁-C₆ alkyl, CONHSO₂aryl,SO₂NHCOaryl, CONHSO₂-C₁-C₆ alkyl, CONHSO₂aryl, NH2, OH, aryl,heteroaryl, C₃ to C₈ cycloalkyl; or saturated or unsaturated 5 to 10membered mono or bicyclic heterocycle containing one heteroatom selectedfrom O, S or NR⁷, wherein C₁-C₆ alkyl is straight or branched,heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; R⁶ is H, C₁ to C₁₈ alkyl optionally substituted with OH; CJ toC₆ alkenyl, C₃ to C₆ alkynyl, C₁ to C₆ perfluoro alkyl, S(O)_(n)-C₁-C₆alkyl S(O)n aryl where n is 0, 1 or 2;, or COheteroaryl, whereinheteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl,S(O)_(n)-C₁-C₆-alkyl, S(O)_(n)-aryl where n is 0, 1 or 2;COO-C₁-C₆-alkyl, COOaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF₃,SO₂Nheteroaryl, SO₂NHCOaryl, CONHSO-C₁-C₆-alkyl, CONHSO₂aryl, aryl, orheteroaryl, where aryl is phenyl or naphthyl, optionally substituted by1 or 2 groups selected independently from halogen, cyano, amino, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 memberedmono or bicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or N—-C₁-C₆ alkyl; alkyl of 1 to 18 carbonatoms, optionally substituted with one or two groups selectedindependently from R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to3 double bonds, optionally substituted with one or two groups selectedindependently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to3 triple bonds, optionally substituted with one or two groups selectedindependently from R⁵; arylalkyl of 7 to 16 carbon atoms, wherein arylis optionally substituted with one or two groups selected independentlyfrom R⁵; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms andheteroaryl contains 1 or 2 heteroatoms selected from O, S or N and isoptionally substituted with one or two groups selected independentlyfrom R⁵; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl isoptionally substituted with one or two groups selected independentlyfrom R⁵; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, whereinthe cycloalkyl or bicycloalkyl group is optionally substituted with oneor two groups selected independently from R⁵; saturated or unsaturatedmono or bicyclic heterocycle containing one heteroatom selected from O,S or N—C₁-C₆ alkyl, optionally substituted with one or two groupsselected independently from R⁵; or R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkylwhere R⁸ and R⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹together with the interposed nitrogen forms a 5-7 membered saturatedheterocyclic ring optionally containing an oxygen atom, wherein the arylgroup is phenyl or naphthyl; or a pharmaceutically acceptable saltthereof.